microtubule-based transport – basic mechanisms, traffic ...journal of cell science 126,...

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Microtubule-based transport – basic mechanisms,traffic rules and role in neurological pathogenesis

Mariella A. M. Franker1 and Casper C. Hoogenraad1,2,*1Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands2Department of Neuroscience, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

*Author for correspondence ([email protected])

Journal of Cell Science 126, 2319–2329� 2013. Published by The Company of Biologists Ltddoi: 10.1242/jcs.115030

SummaryMicrotubule-based transport is essential for neuronal function because of the large distances that must be traveled by various buildingblocks and cellular materials. Recent studies in various model systems have unraveled several regulatory mechanisms and traffic rulesthat control the specificity, directionality and delivery of neuronal cargos. Local microtubule cues, opposing motor activity and cargo-adaptors that regulate motor activity control microtubule-based transport in neurons. Impairment of intracellular transport is detrimental

to neurons and has emerged as a common factor in several neurological disorders. Genetic approaches have revealed strong linksbetween intracellular transport processes and the pathogenesis of neurological diseases in both the central and peripheral nervoussystem. This Commentary highlights recent advances in these areas and discusses the transport defects that are associated with the

development of neurological diseases.

Key words: Brain, Neuron, Neurological disease, Microtubule, Transport, Kinesin, Dynein, Adaptor proteins

IntroductionTo build and maintain highly complex neurons with active

synapses, many basic building blocks – for example, proteins,

lipids and cellular materials, such as mitochondria and synaptic

vesicles – need to be sorted to either axons or dendrites (Kapitein

and Hoogenraad, 2011; Namba et al., 2011; Rolls, 2011). It is

well known that intracellular cargo transport in neurons is driven

by motor proteins that can move directionally along either of two

types of cytoskeletal structures: actin filaments and microtubules

(see Box 1). Actin facilitates motility of motor proteins of the

myosin family, whereas microtubules serve as tracks for two

families of motor proteins, the kinesins and dyneins, which move

towards the microtubule plus-end or minus-end, respectively

(Hirokawa et al., 2009; Schliwa and Woehlke, 2003; Vale, 2003).

Evidence shows that microtubule-based transport mainly

facilitates the long-range transport into distal axons and

dendrites, whereas actin-based transport is important for short-

range transport and delivery of proteins to synapses and growth

cones (Dent et al., 2011; Hoogenraad and Bradke, 2009;

Kneussel and Wagner, 2013).

Although many members of the motor families participate in

neuronal cargo trafficking, the diversity of motor proteins alone is

insufficient to account for the specificity, directionality and timing

of delivery. It has been shown that regulation of transport occurs

through several additional processes, such as activation or

deactivation of motors, selective binding of motors to cargo,

through microtubule-associated proteins (MAPs) and microtubule

post-translational modifications (PTMs) (Akhmanova and

Hammer, 2010; Goldstein et al., 2008; Janke and Bulinski, 2011;

Schlager and Hoogenraad, 2009). How the microtubule-based

transport of specific cargo types is spatially and temporally

regulated in neurons is now an emerging field of investigation.

Neurons are especially vulnerable to defects in transport due to

the extreme length of the neuronal processes. The longest axon in

the human body can be up to 1 meter long, whereas an average

neuronal cell body is ,50 mm. Motor proteins and their regulatorshave crucial roles in the development of many neurological and

neurodegenerative diseases (De Vos et al., 2008; Millecamps and

Julien, 2013). Disruption of intracellular transport can result in

vesicle-trafficking impairments, alter specific cargo interactions

and cause defects in retrograde survival signals, ultimately leading

to neuronal death and loss of brain function (Coleman, 2011;

Perlson et al., 2010; Saxena and Caroni, 2007). Axonal

pathologies, including abnormal accumulations of proteins and

organelles have been observed in patients with Huntington’s,

Parkinson’s and Alzheimer’s disease, and can severely hinder

neuronal transport pathways (Gunawardena and Goldstein,

2005; Millecamps and Julien, 2013). However, whether the

accumulations are the cause or the consequence of transport

defects is unclear, and the causal relationship between

transport impairments and neurodegeneration is unknown. The

identification of mutations in genes involved in neuronal transport

pathways strongly supports the view that defective transport can

directly trigger neurological diseases. Several disruptive mutations

in a- or b-tubulin and microtubule-based motors have been directlylinked to neurological diseases in both the central and peripheral

nervous system (Eschbach and Dupuis, 2011; Millecamps and

Julien, 2013; Tischfield et al., 2011). In this Commentary, we will

discuss the disease-causing mutations in motor and regulatory

proteins that lead to developmental and neurological disorders.

Before doing so, we outline the basic molecular mechanisms that

control neuronal transport and focus on microtubule cues,

bidirectional transport mechanisms and motor adaptors as

regulators of motor activity.

ARTICLE SERIES: Cell Biology and Disease Commentary 2319

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Transport mechanisms in neuronsMicrotubule-based transport is crucial for neuronal survival and

function, both during development and in the adult brain.

Different cellular processes, such as neuronal migration, axon

guidance, the establishment and maintenance of neuronal polarity

and synaptic plasticity, involve many cytoskeletal elements and

transport events that together form the complex cellular networks

of the nervous system and ensure that the proper connections are

made in the brain (Barnes and Polleux, 2009; Conde and Cáceres,

2009; Hoogenraad and Bradke, 2009). In this section, we will

briefly highlight the importance of the cytoskeletal network and

motor protein transport for neuronal development and function

(Fig. 1).

During development of the nervous system, neuron progenitor

cells migrate across the brain to their final destination (Hatten,

1999). Although extracellular factors and adhesion molecules

provide directional cues to direct the migrating cells and guide

axonal growth, cytoskeletal interactions produce the forces that

are necessary for nuclear positioning and neuronal migration

(Gundersen and Worman, 2013; Kuijpers and Hoogenraad, 2011;

Stiess and Bradke, 2011). For example, it has been shown that

actin-based myosin motors and the dynein regulator Lis1 (also

known as PAFAH1B1) are important for pulling the centrosome

and soma forwards during migration (Vallee et al., 2009). Most

neurons polarize during the migration process to form a distinctaxonal and somatodendritic compartment. It is well known that

microtubule-based mechanisms have an active role in determiningneuronal polarity and axonal outgrowth (Hoogenraad andBradke, 2009). For example, stable microtubules can act asspecific transport roads for the trafficking of signaling factors

that participate in neuronal polarization (Arimura and Kaibuchi,2007; Witte and Bradke, 2008). After the polarization anddifferentiation stages, neurons need to maintain their extensively

polarized morphology, and specific components must bedelivered to the correct neuronal compartment. Specifictargeting of different motor–cargo complexes to either the axon

or the dendrites ensures that the cargo is transported correctly(Hirokawa et al., 2009; Kapitein and Hoogenraad, 2011). Recentstudies have found that, although a few kinesins are non-selective, most kinesin motors preferentially target cargos to the

axon (Huang and Banker, 2012) and only dynein transports cargoexclusively into dendrites (Kapitein et al., 2010a). Thecytoskeleton organization in the axon initial segment (AIS) is

also thought to have a role in axonal targeting by preventingvesicles with dendritic cargo from entering the axon (Song et al.,2009; Watanabe et al., 2012). Moreover, mature neurons form

dendritic spines, which are small ‘knob’-shaped extensionsprotruding from the surface of the dendrites. Dendritic spinesare the major post-synaptic sites for excitatory synaptic

transmission (Bourne and Harris, 2008; Kennedy et al., 2005).Several studies have shown that dynamic microtubulesoccasionally enter denditic spines and have a role in spinemorphology and synaptic plasticity (Hoogenraad and

Akhmanova, 2010). Microtubules in spines might influenceactin dynamics and promote the transport of postsynaptic cargos,such as receptors and postsynaptic proteins. Moreover, transport

processes in the axon of neurons in the central and peripheralnervous system are of key importance to distribute the variousbuilding blocks and cellular materials (Hirokawa et al., 2010;

Millecamps and Julien, 2013; Perlson et al., 2010; Saxton andHollenbeck, 2012). Thus, many different microtubule-basedprocesses are actively involved in various phases of neuronaldevelopment and in the mature nervous system.

Microtubule cues steer neuronal transport

Neuronal transport can be directly regulated by the underlying

microtubule cytoskeleton. The local organization ofmicrotubules, MAPs, such as axonal tau, and PTMs all affectfor neuronal transport (Janke and Kneussel, 2010; Verhey and

Hammond, 2009). In axons, anterograde and retrograde transportis directly dictated by the unipolar organization of themicrotubule array (Hirokawa et al., 2009; Hoogenraad andBradke, 2009). However, in dendrites, the microtubules coalesce

into bundles of mixed polarity and a single motor type couldmediate bidirectional cargo transport by switching frommicrotubules in which the minus-end is directed outwards

(minus-end out) to microtubules in which the plus-end isdirected outwards (plus-end out). The anti-parallel microtubuleorganization in dendrites provides a structural framework for the

regulation of cargo trafficking and raises interesting models withregard to neuronal trafficking rules (Kapitein and Hoogenraad,2011; Rolls, 2011). Moreover, the influence of the local

organization of actin cytoskeleton at presynaptic terminals anddendritic spines and its affect on neuronal cargo transport is ofsignificant importance (Hotulainen and Hoogenraad, 2010;

Box 1. Biochemical and biophysical properties ofmotor proteins

The movements of organelles were first observed in the squid

giant axon and, soon after, molecular motors were identified as the

effectors of this transport (Allen et al., 1982; Brady et al., 1982;

Vale et al., 1985). The decades following the discovery of motor

proteins have yielded many important insights into the molecular,

structural and biophysical properties of cytoskeleton-dependent

motor transport. Many motor properties, such as directionality, stall

forces, and step sizes are now well understood based on

controlled in vitro experiments (Block, 2007; Reck-Peterson et al.,

2006; Yildiz et al., 2008). The structure of kinesin was first

demonstrated using electron microscopy (Hirokawa et al., 2009),

and further high-resolution crystallographic structures of the motor

domains have led to detailed insights into how force and

movement are coupled (Carter et al., 2011; Kon et al., 2012;

Kull et al., 1996). Revolutionary single-molecule biophysics

experiments established that kinesin walks with an asymmetric

hand-over-hand stepping mechanism, hydrolyzing a single ATP

molecule per motor step (Asbury et al., 2003; Vale et al., 1996;

Yildiz et al., 2004). For the motor to be processive, there must be a

proper coordination between the two motor heads. It is still a

matter of debate how this coordination, or gating, takes place

(Block, 2007). Motor proteins move unidirectionally with either

plus-end motility (kinesins) or minus-end motility (dyneins).

However, occasional backstepping of motor proteins can occur

and was first observed for dynein (Toba et al., 2006). It has been

postulated that increased flexibility of the dynein structure gives

rise to a diffusional component in the dynein step, causing an

‘irregular’ stepping pattern that allows variable step sizes, back

steps and even sideways steps (DeWitt et al., 2012; Qiu et al.,

2012). Other studies show that kinesins are also capable of ATP-

dependent backstepping when they are biased by load (Carter and

Cross, 2005). In these situations, the neck-linker region plays an

important role in mediating strain between the two motor heads

and in regulating gating (Clancy et al., 2011).

Journal of Cell Science 126 (11)2320

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Kneussel and Wagner, 2013). For example, myosin motors have

been shown to counteract microtubule-based transport and

facilitate the docking of mitochondria to actin filaments

(Saxton and Hollenbeck, 2012). In vitro approaches have

shown that the axonal MAP tau can be used to tune the

relative amounts of plus-end- and minus-end-directed kinesin

transport (Dixit et al., 2008; Vershinin et al., 2007). Low

concentrations of tau facilitate kinesin-mediated transport,

whereas high concentrations of tau, as is found in the distal

parts of the axon, are favorable for dynein-mediated transport.

Such a difference between the effects of tau on kinesin- and

dynein-based motility has not been confirmed in vivo, where

neither overexpression of tau nor tau deletion alters axonal

transport (Morfini et al., 2007; Yuan et al., 2008). Interestingly,

phosphorylated tau is involved in a number of neurological

disorders, such as Alzheimer’s disease, and has recently been

shown to mislocalize to dendritic spines and mediate synaptic

dysfunction (Hoover et al., 2010).

A leading model for driving selective neuronal transport is that

the affinity of motor proteins for microtubules is affected by the

PTMs on the microtubules (Janke and Kneussel, 2010; Verhey

and Hammond, 2009). For example, during neuronal

polarization, it is well known that vectorial membrane

trafficking occurs into the future axon (Bradke and Dotti,

1997), that stable microtubules act as specific transport roads

(Arimura and Kaibuchi, 2007; Witte and Bradke, 2008), and that

kinesin-1 motors accumulate specifically at the tips of axons

(Jacobson et al., 2006; Nakata and Hirokawa, 2003), all

suggesting that kinesin-1 prefers stable microtubules for axonal

cargo transport. Recent work has identified a specific region in

kinesin-1 that is responsible for its preference to bind to

detyrosinated microtubules (Konishi and Setou, 2009). Here,

knockdown of tubulin–tyrosin ligase (TTL) to decrease

tyrosinated microtubules resulted in the redistribution of

kinesin-1 in both axons and dendrites. Other data suggest that

the abundance of GTP-tubulin in microtubules at the AIS

underlies the selective kinesin-1 localization in axons (Nakata

et al., 2011). Therefore, selective transport is probably not

regulated by a single factor but probably by various local cues,

such as a combination of specific microtubule modifications,

associated proteins and tubulin conformations.

Opposing motor activity and bidirectional transport

Many and diverse types of proteins and cellular materials have

been shown to move bidirectionally in cells (Welte, 2004). A

large number of organelles and cytoskeleton proteins, including

Neuronal migration Neuronal polarization Synapse plasticity

Centrosome

Nucleus

+ ++

+

+

+

+ +

––– –

Actin and myosin II produce

contractile force

AIS filtersunwanted cargo

Mixed microtubulesdirect dendritic

transport

+++

––––

+

PSD

Microtubules

–

+

+++

–––

–+

PSD

Microtubules

Radial glial cell

Neuron protrusion

Postmitoticneuron

Postsynapticspine with

actin network

Microtubulesgrow inside

spinesAxon

Dendrites

Actin maintainsspine shapeand scaffold for the PSD

Actinnetwork

Dynein

Dynein and Lis1 produce

pulling force

Translocationof nucleus

Direction ofmigration

Key

A B C

PTMs guideaxonal transport

Microtubule entryinfluences

synaptic activity

Fig. 1. The role of the cytoskeleton during neuronal development and maturation. (A) During maturation, neurons migrate to their final destination in the

brain, establish a highly polarized structure and form chemical synapses that make the connections between the pre- and post-synaptic sites. The cytoskeleton

plays crucial roles throughout these processes. During migration, actin-based myosin II motors and microtubule-based dynein motors generate the pulling and

pushing forces that translocate the nucleus (see also, Vallee et al., 2009). (B) To maintain the highly polarized neuronal structure, different cargos must be

selectively transported to either the somatodendritic or axonal compartment. The panel shows a few important mechanisms that guide neuronal polarity (see also,

Kapitein and Hoogenraad, 2011). Microtubule post-translational modification (PTMs) that are present in the axon (blue) but absent in dendrites (red) specifically

target axonal cargo, whereas microtubule bundles with mixed orientation direct transport in the dendrites. In addition, the axon initial segment (AIS) filters out

dendritic cargo and prevents it from entering the axon. (C) The actin network is the primary component that gives shape to the dendritic spines and forms a

scaffold for the post-synaptic density (PSD). In addition, microtubules have been shown to transiently enter spines (see Hoogenraad and Akhmanova, 2010).

Transport and disease 2321

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endosomes (Deinhardt et al., 2006), autophagosomes (Madayet al., 2012), intermediate filaments (Li et al., 2012) and synaptic

vesicles (Sabo and McAllister, 2003), are known to showbidirectional movement in neuronal axons. Although there aresome differences between the movements of various neuronalcargos, they share common features, such as frequent stopping

and pausing, as well as reversals in direction during transport,and we are beginning to understand the importance of thesemechanisms to achieve appropriate cargo distributions in

neurons. An interesting example from Drosophila shows thatneuropeptide-containing dense core vesicles, which aretransported into the distal axons, initially pass the proximal

boutons, the presynaptic axonal bulges. Excess vesicles circulateback to the soma and are occasionally captured in en passantboutons, ensuring uniform distribution throughout the axon(Wong et al., 2012).

Although bidirectional movement has been observed in almostall cellular systems, it remains a matter of debate how theseprocesses are regulated. In vitro, motor proteins are intrinsically

capable of processively transporting cargo without requiringadditional regulation by other factors. As indicate above, a singletype of motor protein can mediate bidirectional movement on a

mixed network of opposite polarity microtubule bundles, such asthat found in the dendrites (Kapitein et al., 2010a). Anotherinteresting aspect of bidirectional transport is the interplay betweendifferent microtubule motor types. Backwards and forwards

movements are typically observed during neuronal transport;however, net movement in one direction occurs over largedistances in neurons. How is this achieved? One possibility is

that motors with opposite directionality are continuously acting ona cargo and engage in a stochastic ‘tug-of-war’. This can result ineither stalling of the cargo or in bidirectional, salutatory movements

depending on the relative ‘strength’ of the attached motors.Ultimately, one type of motor wins and transports the cargo in itspreferred direction. A recent study using synthetic ‘DNA origami’

found that ensembles of artificial cargo that are composed ofopposite polarity motors are engaged in a tug-of-war, resulting installed cargo (Derr et al., 2012). Modeling has shown that stochastictug-of-war can induce salutatory bidirectional movements (Müller

et al., 2008), and deformations of endosomes during transport invivo in cohort with decreased speeds during transitions betweenanterograde and retrograde transport (Soppina et al., 2009) argue in

favor of this model. In addition, purified neuronal vesicles thatmove along microtubules in vitro show very similar behavior asobserved in vivo, suggesting that all components that are necessary

for transport are strongly attached to the vesicles themselves(Hendricks et al., 2010). It is plausible, however, that motor-adaptor proteins or other signaling proteins that are attached to the

vesicles were co-purified in this study and further regulated theactivity of the motors (Gross, 2003; Welte, 2004).

Thus, although there is evidence that supports a stochastic‘tug-of-war’ hypothesis, the activity of opposing motors appears

to be closely interlinked (Fig. 2). Knockdown of either kinesin ordynein results in impaired transport in both plus- and minus-enddirections in several different cell types (Jolly and Gelfand,

2011), and it has been shown that coupling an active plus-end-directed motor to peroxisomes also induces motility in theopposite direction in Drosophila S2 cells (Ally et al., 2009)

suggesting that motors with opposite directionality directlyactivate each other. Similar results were found in a study onbidirectional movement of mitochondria in Drosophila larval

motor axons (Pilling et al., 2006). In contrast, several otherstudies report that cargo transport in one direction is readily

achieved by selectively targeting a single type of motor protein,and they demonstrate that the activation by a motor with an

opposite directionality is not required. For instance, a robust

unidirectional motility was observed when kinesin motors arerecruited to peroxisomes, even when dynein function was

disrupted (Kapitein et al., 2010b). Furthermore, acute inhibitionof either dynein heavy chain (DHC) or kinesin-1 heavy chain

(KHC, also known as KIF5B) with antibodies has been found

to only impair minus-end- and plus-end-directed motion,respectively (Hendricks et al., 2010; Shubeita et al., 2008).

These apparently contradictory findings could reflect the variouscontrol mechanisms that exist for motor-based protein transport

(Jolly and Gelfand, 2011). As will be discussed below in more

detail, coordination of opposing motors in neurons is a complexprocess that is regulated by several molecular machineries at

various cellular levels.

Motor adaptors as regulators of motor activity

It is becoming increasingly clear that interactions between motorsand their adaptors are a crucial step in selective transport (Fig. 2)

(Akhmanova and Hammer, 2010; Goldstein et al., 2008;

Hirokawa et al., 2010; Schlager and Hoogenraad, 2009). Arecent report studying the axonal transport of vesicles containing

the prion protein (PrPC) showed that the composition of dyneinand kinesin motors is the same in anterograde-directed,

retrograde-directed and stationary vesicles (Encalada et al.,2011). These data suggest that – in addition to local motor

recruitment mechanisms – a stable population of cargo-

associated motors can be modulated by regulatory factors tocontrol anterograde and retrograde transport. Indeed,

microtubule-based transport is extensively controlled byinternal and external factors, and many regulators of dynein

and kinesin motors have been identified. Recent research has

Dynein KinesinAdaptor protein

Cargo

– +

MAPsPTMs

Kinases and phosphatasesRab GTPaseCa2+

Microtubule

Fig. 2. Bidirectional transport. Plus-end-directed kinesin motors and

minus-end-directed dynein motors are attached to the same cargo

simultaneously and can engage in a stochastic ‘tug-of-war’. In addition, these

motors are regulated further to ensure a proper distribution of cargo in living

cells (black arrows). Adaptor proteins mediate the specific binding between

motor proteins and their cargo. Crosstalk between adaptors and other

regulators is also possible, biasing movement in the direction of either

kinesin- (blue arrow) or dynein-mediated movement (green arrow). Several

signaling events, such as local changes in Ca2+ levels, phosphorylation-

dependent signaling and regulated Rab GTPase activity can activate or

deactivate motors or act on adaptor proteins and other regulators. Finally,

motor activity can be regulated by the underlying microtubule cytoskeleton,

including microtubule-associated proteins (MAPs) and microtubule post-

translational modifications (PTMs).


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shown that adaptor proteins that link motors to their cargo canfunction as either activators or inhibitors of motor proteins and

allow for changes in the direction of transport (Akhmanova andHammer, 2010; Schlager and Hoogenraad, 2009). The list ofmolecules that are known to link transport motors to specificneuronal cargos is rapidly expanding. Biochemical and

proteomics approaches, as well as high-throughput yeast two-hybrid screens, have identified more than 100 proteins that areassociated with kinesin-1 in mammals, flies and worms

(Gindhart, 2006). Most of these proteins are cargo moleculesthemselves, but some are adaptor proteins, including scaffoldingproteins and Rab GTPases that regulate neuronal transport. For

example, Jun N-terminal kinase (JNK)-interacting proteins (JIPs)links kinesin-1 to cargo, such as reelin receptor apolipoprotein Ereceptor 2 (ApoER2, also known as LRP8) and phosphorylated b-amyloid precursor protein (APP), and MAP kinase-activating

death domain protein (MADD, also known as DENN or Rab3GDP/GTP exchange factor) acts as an adaptor between kinesin-3motors and synaptic vesicles (Hirokawa et al., 2010; Namba et al.,

2011; Schlager and Hoogenraad, 2009). Moreover, severalsignaling events, such as local changes in Ca2+ levels,phosphorylation-dependent signaling and regulated Rab GTPase

activity, have been found to influence neuronal transport andregulate the loading and unloading of cargo (Fig. 2) (Nambaet al., 2011; Saxton and Hollenbeck, 2012; Schlager and

Hoogenraad, 2009). Here, we will give two examples of bi-directional cargo adaptors that control the balance betweendynein- and kinesin-based transport and regulate selectivetransport in neurons.

Huntingtin, of which the mutated protein is implicated inHuntingon’s disease, acts as a molecular switch between dyneinand kinesin-1 motors (Caviston et al., 2011; Colin et al., 2008).

When huntingtin is phosphorylated, kinesin is recruited tovesicles, thereby biasing their movement along the microtubuletowards the plus-ends. In the unphosphorylated state, kinesin

recruitment to the vesicle is no longer stabilized, and dynein-mediated retrograde motility predominates (Colin et al., 2008).Many other lines of research support the view that kinesin- anddynein-mediated transport is modulated by phosphorylation. For

example, ERK1/2 phosphorylation of dynein intermediate chain(DIC) recruits cytoplasmic dynein to signaling endosomes forretrograde transport in axons (Mitchell et al., 2012). Moreover,

recent studies in Caenorhabditis elegans have shown that twocyclin-dependent kinases, PCT-1 and CDK-5, directly polarizetrafficking of presynaptic components by inhibiting dynein-

mediated retrograde transport and setting the balance betweenanterograde and retrograde motors (Ou et al., 2010). In contrast,in rat sensory neurons, CDK5 phosphorylation of the dynein-

interacting protein NDEL1 stimulates the cargo transportcapacity of dynein (Pandey and Smith, 2011).

Adaptor proteins that interact with the mitochondrial outersurface have been identified, and these are potential candidates to

regulate mitochondria transport throughout the neuron (Saxtonand Hollenbeck, 2012). Recent findings have demonstrated thattwo very similar motor-adaptor proteins, TRAK1 and TRAK2

utilize different machineries to transport mitochondria to axonsand dendrites (van Spronsen et al., 2013). TRAK1 binds to bothkinesin-1 and dynein and directs mitochondria into axons,

whereas TRAK2 predominantly interacts with dynein–dynactinand mediates the dendritic targeting of mitochondria. Theseresults are consistent with the polarized microtubule organization

in neurons (Baas et al., 1988). Microtubules oriented with the

plus-end outwards drive the TRAK1–dynein–kinesin complex

into axons, whereas microtubules with mixed orientations allow

transport of the TRAK2–dynein complex into dendrites.

Interestingly, these data imply that the opposing motors are

closely interlinked in axons but can act independently from one

another in dendrites. The functional differences between TRAK1

and TRAK2 are explained by conformational differences; the

backfolding of TRAK2 affects its interaction with kinesin-1. It is

tempting to speculate that conformational switching of motor

proteins (see Box 2) and motor-adaptor proteins (as described

above) can coordinate bidirectional transport, polarized

trafficking and influence local cargo movements.

Box 2. Intramolecular motor–tail communication

Communication between the motor domain and tail region is an

important aspect of motor protein regulation. Recent evidence

suggests that the tail region of dynein, through its subunits or

associated proteins, controls its own motor activity. In vitro studies

found that the legs at odd angles (Loa) mutation F580Y in the tail

of the cytoplasmic dynein heavy chain (Hafezparast et al., 2003)

inhibits motor processivity (Ori-McKenney et al., 2010). In addition,

dynein-associated protein NudE (NDE1) and Lis1 are involved in

the interaction between the tail and motor domains of dynein (Ori-

McKenney et al., 2010; Zylkiewicz et al., 2011). NudE–Lis1-

mediated communication appears to be achieved through a

significantly different mechanism from the folding mechanism for

myosin V and some kinesins, which occurs through direct

intramolecular interactions between tail and motor domains (Adio

et al., 2006; Siththanandan and Sellers, 2011). Kinesin-1

undergoes a conformational change that brings the motor

domain in close contact with its tail region as shown by

sedimentation analysis (Hackney et al., 1992). This folded,

inactive conformation of kinesin-1 blocks processive motor

movement (Cai et al., 2007). The crystal structure of kinesin-1

and subsequent biochemical experiments suggest that steric

hindrance is not the cause of inhibition, but that instead the tail

region restrains ADP release (Kaan et al., 2011). Whereas binding

to cargo was initially proposed to unfold kinesin-1 and activate its

motility (Coy et al., 1999), it is now thought that motors can be

present in an inhibited state on the cargo surface and might

alternate between active and inactive conformations in response

to external signals (Blasius et al., 2007). In addition, single-

molecule in vitro studies using quantum dots have shown that

when kinesin-1 is in a folded inhibited state it is able to passively

diffuse along microtubules (Lu et al., 2009). It is plausible that the

ability to diffuse along microtubules is a general feature of

molecular motors. Similar mechanisms have been described for

the kinesin-5 family member Eg5 (also known as KIF11), which is

involved in positioning of the mitotic spindle (Kapitein et al., 2008),

for KIF1A, a kinesin-3 family member (Hammond et al., 2009),

and for MCAK, a kinesin-13 microtubule-depolymerizing motor

(Helenius et al., 2006). The motor properties described in Box 1,

such as motor back-stepping, motor-neck–tail communication and

diffusion might allow motors to slow down and step around

obstacles to resolve ‘road blocks’ or ‘traffic jams’, and to switch to

other cytoskeletal tracks without exchanging the motors attached

to the cargo. Indeed, in disease models of Alzheimer’s and motor

neuron disease, it appears that only a small fraction of cargos are

trapped in these ‘traffic jams’, suggesting that motors could

possibly bypass these blockages (Pilling et al., 2006; Shemesh

et al., 2008).


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Microtubule transport and diseaseAs microtubule-based transport is fundamental to the

development and function of mature neurons, defects in

neuronal transport pathways are likely to cause neuronal

diseases (Chevalier-Larsen and Holzbaur, 2006; De Vos et al.,

2008; Hirokawa et al., 2010; Salinas et al., 2008). Although many

studies suggest that transport pathways have a major role in the

onset and progression of various human developmental and

neurological disorders, the causal relationship between transport

impairments and neurodegeneration is largely unclear

(Gunawardena and Goldstein, 2005; Millecamps and Julien,

2013). Several kinesin-knockout mice display specific

neurological phenotypes, such as epilepsy and hydrocephalus

(Nakajima et al., 2012; Niwa et al., 2012), and kinesin-2-related

ciliopathy, causing hydrocephalus and disturbance in

dorsoventral patterning of the neural tube (Hirokawa et al.,

2012). The identification of mutations in genes involved in

neuronal transport pathways strengthens the direct link between

transport defects and human neurological diseases (Table 1 and

Fig. 3). In this section, we will discuss a few examples of

how mutations in different tubulin isotypes and motor proteins

might lead to defective neuronal transport and trigger

neurodegeneration.

One way to impair neuronal transport is to disrupt the

underlying microtubule network (Baas et al., 2005; Conde and

Cáceres, 2009; Janke and Bulinski, 2011; Lumb et al., 2012;

Tischfield et al., 2011). Mutations in a- and b-tubulin-encodinggenes have been identified in patients suffering from a wide

spectrum of neurological disorders, ranging from microcephaly

and seizures to intellectual disabilities and peripheral neuropathy.

For instance, mutations in the a-tubulin isotype VIII gene TUBA8cause polymicrogyria with optic nerve hypoplasia (Abdollahi

et al., 2009), and mutations in the b-tubulin isotype II geneTUBB2 result in asymmetrical polymicrogyria (Jaglin et al.,

2009). Moreover, in mice, mutations in the tubulin-specific

chaperone Tbce lead to a severe deficiency of microtubules in

distal axons in progressive motor neuronopathy (Martin et al.,

2002; Schaefer et al., 2007), and mutations in the microtubule

assembly and severing protein spastin 4 (SPG4) cause hereditary

spastic paraplegia in humans (Magariello et al., 2013; Nanetti

et al., 2012). In addition, missense mutations in TUBB3, which

encodes the neuron-specific b-tubulin isotype III, cause a more

Table 1. Mutations in transport proteins underlying neurological disorders

Mutant protein Functional role Functional defect Disease Reference

Mutations in motorsDYNC1H1 (dynein) Vesicular and organelle

transportDefects in neuronal

migration; late-onsetmotor neuron degeneration

Lissencephaly; Charcot–Marie–Tooth disease 2 (CMT2);Perry syndrome; Spinalmuscular atropy

(Braunstein et al., 2010; Harmset al., 2010; Weedon et al.,2011; Willemsen et al.,2012)

KIF5A Vesicular and organelletransport

Impaired axonal transport Hereditary spastic paraplegia(SPG10); CMT2

(Crimella et al., 2012; Fügeret al., 2012)

KIF1B Synaptic vesicle transport,mitochondrial transport

Reduced transport ofsynaptic vesicle proteins

CMT2 (Gentil and Cooper, 2012;Zhao et al., 2001)

KIF21A Axonal transport of K+-dependent Na+/Ca2+

exchanger (NCKX2)

Atrophy of ocular motormuscles

Congenital fibrosis of theextraocular muscle (CFEOM)

(Desai et al., 2012; Lee et al.,2012)

Motor adaptor and regulatorprotein mutationsDCTN1/p150glued

(dynactin)Dynein regulation Impaired axonal transport;

axonal swelling; synapseretraction

Motor neuron disease;amytrophic lateral sclerosis(ALS); Perry syndrome

(Newsway et al., 2010;Stockmann et al., 2012;Uribe, 2010)

LIS1 (PAFAH1B1) Coupling of nucleus tocentrosome duringneuronal migration;dynein regulator

Impaired neuronal migration;reduced axonal transport

Lissencephaly (Mokánszki et al., 2012)

Cytoskeletal mutationsTUBA1A a-tubulin isoform Neuronal migration Lissencephaly (Cushion et al., 2013; Hikita

et al., 2013; Tischfield et al.,2011)

TUBA8 a-tubulin isoform Local cell positioningduring cerebral corticaldevelopment

Polymicrogyria with optic nervehypoplasia

(Abdollahi et al., 2009;Tischfield et al., 2011)

TUBB2B b-tubulin isoform Neuronal migration Asymmetricalpolymicrogyria

(Cushion et al., 2013;Romaniello et al., 2012;Tischfield et al., 2011)

TUBB3 b-tubulin isoform(neuron specific)

Neuronal migrations andaxon guidance defects

CFEOMFacial paralysisLate-onset axonal

sensorimotor polyneuropathy

(Poirier et al., 2010; Tischfieldet al., 2011)

TUBB5 b-tubulin isoform Neuronal migration Microcephaly (Breuss et al., 2012)TBCE Tubulin chaperone Impaired maintenance of

microtubules in motoraxons

Progressive motorneuropathy

(Martin et al., 2002; Schaeferet al., 2007)

SPG4 (spastin) Microtubule severer Synaptic growth andneurotransmission defects

Hereditary spastic paraplegia (Magariello et al., 2013;Nanetti et al., 2012)

The table is limited to mutations in motor proteins and associated proteins that have a strong genetic link to neurological disease.


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diffuse spectrum of brain malformations and neurological

disabilities, and certain phenotypes often segregate with

particular amino acid substitutions (Poirier et al., 2010;

Tischfield et al., 2010). A recent study directly investigated

whether TUBB3 mutations impair microtubule-based transport in

neurons and found that of the 14 b-tubulin mutants tested, onlytwo TUBB3 mutations directly disrupt the interaction with

kinesin motors and subsequently impair axonal transport (Niwa

et al., 2013). The other mutations in b-tubulin III probably disturbother microtubule properties, such as the stability of a-tubulin–b-tubulin heterodimers or other characteristics, including the

(de)polymerization properties of tubulin, microtubule dynamics

or MAP interactions (Tischfield et al., 2011).

Several mutations in microtubule-based motors have also been

directly linked to neurological diseases. These motor mutations

can affect specific neuronal transport routes, or involve multiple

cargos and impair multiple pathways (Chevalier-Larsen and

Holzbaur, 2006; Hirokawa et al., 2010). Kinesin motor proteins

have been directly linked to several neurodegenerative diseases.

Mutations in the motor and stalk domain of the kinesin-1 family

member KIF5A cause hereditary spastic paraplegia and Charcot–

Marie–Tooth (CMT) disease type 2 (Crimella et al., 2012; Reid

et al., 2002). Mutations in the KIF21A stalk region have been

shown to be the underlying cause of congenital fibrosis of the

extraocular muscle type 1 (CFEOM1) (Yamada et al., 2003),

which is associated with defects in the oculomotor nerve and

results in an inability to move or raise the eyes. A recent study

showed that knockdown of KIF21A causes the dysregulation of

Ca2+ at axonal boutons owing to inhibited transport of NCKX2, a

K+-dependent Na+-exchanger that is involved in Ca2+ clearance

in the large axon terminals of central neurons (Lee et al., 2012).

Moreover, a mutation in KIF1B-b, a kinesin-3 family member,was identified in CMT2 patients (Zhao et al., 2001). The

heterogyzous Kif1b-knockout mouse presents similar phenotypes,

including a chronic peripheral neuropathy with progressive motor

weakness and motor coordination, and investigation of its sciatic

nerves revealed that transport of synaptic vesicles to the distal

axon is impaired. The KIF1B-b mutation is not the only gene thatis linked to CMT2, because, so far, mutations in more than 30

genes have been identified that cause CMT disease, several of

which are linked to specific transport pathways (Gentil and

Cooper, 2012).

Cytoplasmic dynein has a pivotal role in neuronal trafficking

because it is the only microtubule-based motor protein with

minus-end-directed motility (Pfister et al., 2006). Indeed,

mutations in the dynein heavy chain gene DHC1H1 lead to

striatal atrophy, neuronal migration defects, intellectual

disability, CMT and spinal muscular atrophy (SMA)

(Braunstein et al., 2010; Harms et al., 2010; Weedon et al.,

2011; Willemsen et al., 2012). Consistent with these findings,

mutations in dynein in Drosophila and C. elegans result in

intracellular protein aggregates and behavioral abnormalities,

including locomotor impairment (Eaton et al., 2002; Koushika

et al., 2004). Furthermore, disrupting the function of dynein in

Axon

Dendrite

PolymicrogyriaLissencephalyCongenital fibrosis ofthe extraocular muscle(CFEOM)Motor neuropathy

paraplegia (HSP)Microtubule

α-tubulinβ-tubulin

TUBA8TUBA1A TUBB3

–

TUBB2B

TBCE

Spastin

TUBB5

Microencephaly

Dendrite

Charcot–Marie– Tooth 2 (CMT2)Perry syndromeDynein Dynactin

Lis1 Spinal muscular atrophy (SMA)

Amyotrohic lateral sclerosis (ALS) paraplegia (HSP)

Charcot–Marie–Tooth 2 (CMT2)

Congenital fibrosis ofthe extraocular muscle (CFEOM)

KIF1B

KIF5A KIF21A

Lissencenphaly

+

Tubulin

DyneinKinesin

– +Microtubule

– +Microtubule

– +Microtubule

Hereditary spastic

Cargo

Mitochondrion

Hereditary spastic

Fig. 3. Major transport defects in

neurons and neurological diseases.

Impaired neuronal transport can be

caused by disruption of the microtubule

network, by changes in the processivity

or activation of motor proteins, or by

effects on the binding of cargo to motor

proteins. As illustrated here, interfering

with either of these regulatory

mechanisms gives rise to neuronal

transport defects and often leads to

variety of neurological disease

phenotypes. For example, mutations in

the kinesin motor protein KIF5A have

been linked to dominant forms of the

hereditary spastic paraplegia (HSP) and

Charcot–Marie–Tooth disease type 2

(CMT2) in humans, whereas mutations in

b-tubulin isotype III gene TUBB3 leads

to the ocular motility disorder, congenital

fibrosis of the extraocular muscles type 3

(CFEOM3). Furthermore, mutations in

dynein and its accessory proteins

dynactin and Lis1 have been associated

to spinal muscular atrophy (SMA),

amytrophic lateral sclerosis (ALS)-like

motor neuron degeneration and early-

onset parkinsonism called Perry

syndrome.


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motor neurons in mice causes amyotrophic lateral sclerosis

(ALS)-like features (LaMonte et al., 2002; Teuling et al., 2008).

Mice strains with spontaneous heterozygous mutations in

DYNC1H1, such as the ‘legs at odd angles’ (Loa) and

‘cramping 1’ (Cra1) alleles, also show late-onset motor neuron

degeneration (Hafezparast et al., 2003. Recent in vitro studies

found that the Loa mutation F580Y in the tail of the mouse

cytoplasmic dynein heavy chain inhibits motor processivity (Ori-

McKenney et al., 2010). These data indicate that communication

between the motor domain and tail region is another important

aspect of motor regulation (see Box 2). Dynein is regulated by a

number of factors, such as LIS1, which, when disrupted, have

also been implicated in neurodevelopmental and neurological

diseases (Kardon and Vale, 2009). For example, missense

mutations in the dynactin gene (DCTN1) that encodes the

p150glued subunit of dynactin have been associated with both

familial and sporadic ALS (Münch et al., 2004; Puls et al., 2003;

Puls et al., 2005). Neuronal expression of mutant p150glued in

mice causes motor neuron disease, which is characterized by

defects in vesicular transport, axonal swelling and axo-terminal

degeneration (Chevalier-Larsen and Holzbaur, 2006; Lai et al.,

2007; Laird et al., 2008). It has recently been hypothesized that

the disease-causing mutations in the CAP-Gly domain of

p150glued inhibit the binding of dynactin at microtubule plus-

ends, thereby abolishing the initiation of retrograde axonal

transport (Lloyd et al., 2012; Moughamian and Holzbaur, 2012).

Interestingly, different mutations in the same microtubule-

binding domain of p150glued cause Perry syndrome, a

Parkinson-like disease that is characterized by the loss of

dopaminergic neurons (Farrer et al., 2009).

Another well-known neurological disorder that has been linked

to the dynein motor complex is lissencephaly, a developmental

brain malformation in which the surface of the brain is smooth

rather than full of folds and the disease subsequently leads to

seizures and mental retardation (Kato and Dobyns, 2003;

Kuijpers and Hoogenraad, 2011; Métin et al., 2008; Wynshaw-

Boris et al., 2010). Perturbing the levels of Lis1 causes defects in

microtubule-based processes, such as nuclear migration and

cargo transport (Pandey and Smith, 2011; Tanaka et al., 2004;

Tsai et al., 2007). Lis1 has been found to function in microtubule-

based trafficking by preparing dynein-coupled cargos for

transport by targeting it to the plus-ends of microtubules

(Egan et al., 2012; Li et al., 2005; McKenney et al., 2010; Yi

et al., 2011). Recent single-molecule and structural studies

demonstrated that Lis1 binds in between the ATPase and

microtubule-binding domains of dynein and prolongs its

attachments to microtubules (Huang and Banker, 2012). Lis1

– at least in yeast – is not required for dynein-based cargo

motility once dynein is moving, but it instead has a general role

in initiating dynein-driven motility (Egan et al., 2012). The

numerous mutations in dynein, dynactin and associated

proteins, and the broad spectrum of phenotypes, demand a

clinical re-classification of dynein-related disorders, where the

neurological phenotype must be defined not only genetically

but also by the specific cellular effects. Future studies should

aim at dissecting the complexities of the dynein structure and

its interaction with associated proteins to find out the various

mechanisms by which disease-related dynein mutations disrupt

transport functions in the central and peripheral nervous

system.

ConclusionsTransport is essential for many different processes in neurons in

order to establish and maintain polarity, for axon guidance and

regeneration, as well as for synaptic plasticity, both during

developmental stages and in the adult brain. Although the

biochemical mechanisms underlying motor proteins-based

transport are well understood, much of the regulatory processes

that act on these motors are still unknown. Many studies now

show the importance of these regulatory pathways and emphasize

the role of adaptor proteins and regulators, in particular with

relevance to diseases of the brain. However, a number of

questions remain. How does a motor find the appropriate cargo?

How many different motor types are attached to a specific cargo?

How does the cargo know when to stop and ‘unload’ its content?

Disruption of transport is thought to be an early and perhaps

causative event in Alzheimer’s disease, Huntington’s disease and

ALS, in which abnormal accumulations of cytoskeleton proteins

and organelles in axons have been observed (De Vos et al., 2008;

Millecamps and Julien, 2013). The pivotal challenges are to

identify the molecular and cellular cause of human brain

disorders that arise from intracellular transport defects and to

determine how changes in motor protein regulation impact on

neuronal structure and function. Defects in transport lead to many

different and stress-related responses in cells, making it difficult

to elucidate the exact mechanisms underlying a disease. To

better understand intracellular transport in neurons, a better

understanding of the organization and dynamics of underlying

microtubule cytoskeleton, as well as novel approaches to control

and manipulate neuronal cargo transport are required (Jenkins

et al., 2012; Kapitein et al., 2010a). The spatial and temporal

arrangement of transport complexes and the cytoskeleton along

which they move is of crucial importance in order to understand

how multiple motors can regulate the transport and delivery of

specific cargos. These findings could potentially lead to new

tools that will be useful when investigating the transport

machinery in neurodegenerative disease models. Future studies

using genetic disease mouse models will advance our

understanding of the neurodegenerative disorders. Functional

assays in primary neuronal cells from mouse models or neurons

developed from inducible pluripotent stem (IPS) cells of patients

(Abeliovich and Doege, 2009) will further help to elucidate the

specific disease mechanisms. Moreover, advances in the

discovery and synthesis of small molecules that can modulate

microtubule-based processes in the brain might offer new

therapeutic paradigms to treat neurological defects and

intervene in neurodegenerative processes. The use of the

microtubule-stabilizing drug taxol to decrease fibrotic scar

formation and promote axon regeneration in rodents after

spinal cord injury (Ertürk et al., 2007; Hellal et al., 2011) is a

promising step in this direction, and other similar approaches

hopefully will follow.

AcknowledgementsWe thank Lukas Kapitein and Phebe Wulf for critical reading of themanuscript.

FundingThe work of our laboratories is supported by Het Prinses BeatrixSpierfonds; the Netherlands Organization for Scientific Research(NWO-ALW-VICI); the Netherlands Organization for HealthResearch and Development (ZonMW-TOP); the European Science


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Foundation (EURYI); and the EMBO Young Investigators Program(YIP).

ReferencesAbdollahi, M. R., Morrison, E., Sirey, T., Molnar, Z., Hayward, B. E., Carr, I. M.,

Springell, K., Woods, C. G., Ahmed, M., Hattingh, L. et al. (2009). Mutation of thevariant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia.Am. J. Hum. Genet. 85, 737-744.

Abeliovich, A. and Doege, C. A. (2009). Reprogramming therapeutics: iPS cellprospects for neurodegenerative disease. Neuron 61, 337-339.

Adio, S., Reth, J., Bathe, F. and Woehlke, G. (2006). Review: regulation mechanismsof Kinesin-1. J. Muscle Res. Cell Motil. 27, 153-160.

Akhmanova, A. and Hammer, J. A., III (2010). Linking molecular motors tomembrane cargo. Curr. Opin. Cell Biol. 22, 479-487.

Allen, R. D., Metuzals, J., Tasaki, I., Brady, S. T. and Gilbert, S. P. (1982). Fastaxonal transport in squid giant axon. Science 218, 1127-1129.

Ally, S., Larson, A. G., Barlan, K., Rice, S. E. and Gelfand, V. I. (2009). Opposite-polarity motors activate one another to trigger cargo transport in live cells. J. CellBiol. 187, 1071-1082.

Arimura, N. and Kaibuchi, K. (2007). Neuronal polarity: from extracellular signals tointracellular mechanisms. Nat. Rev. Neurosci. 8, 194-205.

Asbury, C. L., Fehr, A. N. and Block, S. M. (2003). Kinesin moves by an asymmetrichand-over-hand mechanism. Science 302, 2130-2134.

Baas, P. W., Deitch, J. S., Black, M. M. and Banker, G. A. (1988). Polarity orientationof microtubules in hippocampal neurons: uniformity in the axon and nonuniformity inthe dendrite. Proc. Natl. Acad. Sci. USA 85, 8335-8339.

Baas, P. W., Karabay, A. and Qiang, L. (2005). Microtubules cut and run. Trends CellBiol. 15, 518-524.

Barnes, A. P. and Polleux, F. (2009). Establishment of axon-dendrite polarity indeveloping neurons. Annu. Rev. Neurosci. 32, 347-381.

Blasius, T. L., Cai, D., Jih, G. T., Toret, C. P. and Verhey, K. J. (2007). Two bindingpartners cooperate to activate the molecular motor Kinesin-1. J. Cell Biol. 176, 11-17.

Block, S. M. (2007). Kinesin motor mechanics: binding, stepping, tracking, gating, andlimping. Biophys. J. 92, 2986-2995.

Bourne, J. N. and Harris, K. M. (2008). Balancing structure and function athippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47-67.

Bradke, F. and Dotti, C. G. (1997). Neuronal polarity: vectorial cytoplasmic flowprecedes axon formation. Neuron 19, 1175-1186.

Brady, S. T., Lasek, R. J. and Allen, R. D. (1982). Fast axonal transport in extrudedaxoplasm from squid giant axon. Science 218, 1129-1131.

Braunstein, K. E., Eschbach, J., Ròna-Vörös, K., Soylu, R., Mikrouli, E., Larmet,

Y., René, F., Gonzalez De Aguilar, J. L., Loeffler, J. P., Müller, H. P. et al. (2010).A point mutation in the dynein heavy chain gene leads to striatal atrophy andcompromises neurite outgrowth of striatal neurons. Hum. Mol. Genet. 19, 4385-4398.

Breuss, M., Heng, J. I., Poirier, K., Tian, G., Jaglin, X. H., Qu, Z., Braun, A.,

Gstrein, T., Ngo, L., Haas, M. et al. (2012). Mutations in the b-tubulin gene TUBB5cause microcephaly with structural brain abnormalities. Cell Rep. 2, 1554-1562.

Cai, D., Hoppe, A. D., Swanson, J. A. and Verhey, K. J. (2007). Kinesin-1 structuralorganization and conformational changes revealed by FRET stoichiometry in livecells. J. Cell Biol. 176, 51-63.

Carter, N. J. and Cross, R. A. (2005). Mechanics of the kinesin step. Nature 435, 308-312.

Carter, A. P., Cho, C., Jin, L. and Vale, R. D. (2011). Crystal structure of the dyneinmotor domain. Science 331, 1159-1165.

Caviston, J. P., Zajac, A. L., Tokito, M. and Holzbaur, E. L. (2011). Huntingtincoordinates the dynein-mediated dynamic positioning of endosomes and lysosomes.Mol. Biol. Cell 22, 478-492.

Chevalier-Larsen, E. and Holzbaur, E. L. (2006). Axonal transport and neurodegenerativedisease. Biochim. Biophys. Acta 1762, 1094-1108.

Clancy, B. E., Behnke-Parks, W. M., Andreasson, J. O., Rosenfeld, S. S. and Block,S. M. (2011). A universal pathway for kinesin stepping. Nat. Struct. Mol. Biol. 18,1020-1027.

Coleman, M. (2011). Molecular signaling how do axons die? Adv. Genet. 73, 185-217.

Colin, E., Zala, D., Liot, G., Rangone, H., Borrell-Pagès, M., Li, X. J., Saudou,

F. and Humbert, S. (2008). Huntingtin phosphorylation acts as a molecular switchfor anterograde/retrograde transport in neurons. EMBO J. 27, 2124-2134.

Conde, C. and Cáceres, A. (2009). Microtubule assembly, organization and dynamicsin axons and dendrites. Nat. Rev. Neurosci. 10, 319-332.

Coy, D. L., Hancock, W. O., Wagenbach, M. and Howard, J. (1999). Kinesin’s taildomain is an inhibitory regulator of the motor domain. Nat. Cell Biol. 1, 288-292.

Crimella, C., Baschirotto, C., Arnoldi, A., Tonelli, A., Tenderini, E., Airoldi, G.,

Martinuzzi, A., Trabacca, A., Losito, L., Scarlato, M. et al. (2012). Mutations inthe motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonalCharcot-Marie-Tooth type 2. Clin. Genet. 82, 157-164.

Cushion, T. D., Dobyns, W. B., Mullins, J. G., Stoodley, N., Chung, S. K., Fry, A. E.,

Hehr, U., Gunny, R., Aylsworth, A. S., Prabhakar, P. et al. (2013). Overlappingcortical malformations and mutations in TUBB2B and TUBA1A. Brain 136, 536-548.

De Vos, K. J., Grierson, A. J., Ackerley, S. and Miller, C. C. (2008). Role of axonaltransport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151-173.

Deinhardt, K., Salinas, S., Verastegui, C., Watson, R., Worth, D., Hanrahan, S.,Bucci, C. and Schiavo, G. (2006). Rab5 and Rab7 control endocytic sorting along theaxonal retrograde transport pathway. Neuron 52, 293-305.

Dent, E. W., Gupton, S. L. and Gertler, F. B. (2011). The growth cone cytoskeleton inaxon outgrowth and guidance. Cold Spring Harb. Perspect. Biol. 3, a001800.

Derr, N. D., Goodman, B. S., Jungmann, R., Leschziner, A. E., Shih, W. M. andReck-Peterson, S. L. (2012). Tug-of-war in motor protein ensembles revealed with aprogrammable DNA origami scaffold. Science 338, 662-665.

Desai, J., Velo, M. P., Yamada, K., Overman, L. M. and Engle, E. C. (2012).Spatiotemporal expression pattern of KIF21A during normal embryonic developmentand in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Gene Expr.Patterns 12, 180-188.

DeWitt, M. A., Chang, A. Y., Combs, P. A. and Yildiz, A. (2012). Cytoplasmic dyneinmoves through uncoordinated stepping of the AAA+ ring domains. Science 335, 221-225.

Dixit, R., Ross, J. L., Goldman, Y. E. and Holzbaur, E. L. (2008). Differentialregulation of dynein and kinesin motor proteins by tau. Science 319, 1086-1089.

Eaton, B. A., Fetter, R. D. and Davis, G. W. (2002). Dynactin is necessary for synapsestabilization. Neuron 34, 729-741.

Egan, M. J., Tan, K. and Reck-Peterson, S. L. (2012). Lis1 is an initiation factor fordynein-driven organelle transport. J. Cell Biol. 197, 971-982.

Encalada, S. E., Szpankowski, L., Xia, C. H. and Goldstein, L. S. (2011). Stablekinesin and dynein assemblies drive the axonal transport of mammalian prion proteinvesicles. Cell 144, 551-565.

Ertürk, A., Hellal, F., Enes, J. and Bradke, F. (2007). Disorganized microtubulesunderlie the formation of retraction bulbs and the failure of axonal regeneration.J. Neurosci. 27, 9169-9180.

Eschbach, J. and Dupuis, L. (2011). Cytoplasmic dynein in neurodegeneration.Pharmacol. Ther. 130, 348-363.

Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dächsel, J. C., Stoessl, A. J.,

Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F. et al. (2009).DCTN1 mutations in Perry syndrome. Nat. Genet. 41, 163-165.

Füger, P., Sreekumar, V., Schüle, R., Kern, J. V., Stanchev, D. T., Schneider, C. D.,Karle, K. N., Daub, K. J., Siegert, V. K., Flötenmeyer, M. et al. (2012). Spasticparaplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonaltransport in a Drosophila HSP model. PLoS Genet. 8, e1003066.

Gentil, B. J. and Cooper, L. (2012). Molecular basis of axonal dysfunction and trafficimpairments in CMT. Brain Res. Bull. 88, 444-453.

Gindhart, J. G. (2006). Towards an understanding of kinesin-1 dependent transportpathways through the study of protein-protein interactions. Brief Funct. GenomicProteomic 5, 74-86.

Goldstein, A. Y., Wang, X. and Schwarz, T. L. (2008). Axonal transport and thedelivery of pre-synaptic components. Curr. Opin. Neurobiol. 18, 495-503.

Gross, S. P. (2003). Dynactin: coordinating motors with opposite inclinations. Curr.Biol. 13, R320-R322.

Gunawardena, S. and Goldstein, L. S. (2005). Polyglutamine diseases and transportproblems: deadly traffic jams on neuronal highways. Arch. Neurol. 62, 46-51.

Gundersen, G. G. and Worman, H. J. (2013). Nuclear positioning. Cell 152, 1376-1389.

Hackney, D. D., Levitt, J. D. and Suhan, J. (1992). Kinesin undergoes a 9 S to 6 Sconformational transition. J. Biol. Chem. 267, 8696-8701.

Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A.,

Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S. et al. (2003).Mutations in dynein link motor neuron degeneration to defects in retrograde transport.Science 300, 808-812.

Hammond, J. W., Cai, D., Blasius, T. L., Li, Z., Jiang, Y., Jih, G. T., Meyhofer,

E. and Verhey, K. J. (2009). Mammalian Kinesin-3 motors are dimeric in vivo andmove by processive motility upon release of autoinhibition. PLoS Biol. 7, e72.

Harms, M. B., Allred, P., Gardner, R., Jr, Fernandes Filho, J. A., Florence, J.,Pestronk, A., Al-Lozi, M. and Baloh, R. H. (2010). Dominant spinal muscularatrophy with lower extremity predominance: linkage to 14q32. Neurology 75, 539-546.

Hatten, M. E. (1999). Central nervous system neuronal migration. Annu. Rev. Neurosci.22, 511-539.

Helenius, J., Brouhard, G., Kalaidzidis, Y., Diez, S. and Howard, J. (2006). Thedepolymerizing kinesin MCAK uses lattice diffusion to rapidly target microtubuleends. Nature 441, 115-119.

Hellal, F., Hurtado, A., Ruschel, J., Flynn, K. C., Laskowski, C. J., Umlauf, M.,Kapitein, L. C., Strikis, D., Lemmon, V., Bixby, J. et al. (2011). Microtubulestabilization reduces scarring and causes axon regeneration after spinal cord injury.Science 331, 928-931.

Hendricks, A. G., Perlson, E., Ross, J. L., Schroeder, H. W., III, Tokito, M. andHolzbaur, E. L. (2010). Motor coordination via a tug-of-war mechanism drivesbidirectional vesicle transport. Curr. Biol. 20, 697-702.

Hikita, N., Hattori, H., Kato, M., Sakuma, S., Morotomi, Y., Ishida, H., Seto, T.,

Tanaka, K., Shimono, T., Shintaku, H. et al. (2013). A case of TUBA1A mutationpresenting with lissencephaly and Hirschsprung disease. Brain Dev.

Hirokawa, N., Noda, Y., Tanaka, Y. and Niwa, S. (2009). Kinesin superfamily motorproteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682-696.

Hirokawa, N., Niwa, S. and Tanaka, Y. (2010). Molecular motors in neurons: transportmechanisms and roles in brain function, development, and disease. Neuron 68, 610-638.

Hirokawa, N., Tanaka, Y. and Okada, Y. (2012). Cilia, KIF3 molecular motor andnodal flow. Curr. Opin. Cell Biol. 24, 31-39.

Hoogenraad, C. C. and Akhmanova, A. (2010). Dendritic spine plasticity: newregulatory roles of dynamic microtubules. Neuroscientist 16, 650-661.


http://dx.doi.org/10.1016/j.ajhg.2009.10.007http://dx.doi.org/10.1016/j.ajhg.2009.10.007http://dx.doi.org/10.1016/j.ajhg.2009.10.007http://dx.doi.org/10.1016/j.ajhg.2009.10.007http://dx.doi.org/10.1016/j.neuron.2009.01.024http://dx.doi.org/10.1016/j.neuron.2009.01.024http://dx.doi.org/10.1007/s10974-005-9054-1http://dx.doi.org/10.1007/s10974-005-9054-1http://dx.doi.org/10.1016/j.ceb.2010.04.008http://dx.doi.org/10.1016/j.ceb.2010.04.008http://dx.doi.org/10.1126/science.6183744http://dx.doi.org/10.1126/science.6183744http://dx.doi.org/10.1083/jcb.200908075http://dx.doi.org/10.1083/jcb.200908075http://dx.doi.org/10.1083/jcb.200908075http://dx.doi.org/10.1038/nrn2056http://dx.doi.org/10.1038/nrn2056http://dx.doi.org/10.1126/science.1092985http://dx.doi.org/10.1126/science.1092985http://dx.doi.org/10.1073/pnas.85.21.8335http://dx.doi.org/10.1073/pnas.85.21.8335http://dx.doi.org/10.1073/pnas.85.21.8335http://dx.doi.org/10.1016/j.tcb.2005.08.004http://dx.doi.org/10.1016/j.tcb.2005.08.004http://dx.doi.org/10.1146/annurev.neuro.31.060407.125536http://dx.doi.org/10.1146/annurev.neuro.31.060407.125536http://dx.doi.org/10.1083/jcb.200605099http://dx.doi.org/10.1083/jcb.200605099http://dx.doi.org/10.1529/biophysj.106.100677http://dx.doi.org/10.1529/biophysj.106.100677http://dx.doi.org/10.1146/annurev.neuro.31.060407.125646http://dx.doi.org/10.1146/annurev.neuro.31.060407.125646http://dx.doi.org/10.1016/S0896-6273(00)80410-9http://dx.doi.org/10.1016/S0896-6273(00)80410-9http://dx.doi.org/10.1126/science.6183745http://dx.doi.org/10.1126/science.6183745http://dx.doi.org/10.1093/hmg/ddq361http://dx.doi.org/10.1093/hmg/ddq361http://dx.doi.org/10.1093/hmg/ddq361http://dx.doi.org/10.1093/hmg/ddq361http://dx.doi.org/10.1016/j.celrep.2012.11.017http://dx.doi.org/10.1016/j.celrep.2012.11.017http://dx.doi.org/10.1016/j.celrep.2012.11.017http://dx.doi.org/10.1083/jcb.200605097http://dx.doi.org/10.1083/jcb.200605097http://dx.doi.org/10.1083/jcb.200605097http://dx.doi.org/10.1038/nature03528http://dx.doi.org/10.1038/nature03528http://dx.doi.org/10.1126/science.1202393http://dx.doi.org/10.1126/science.1202393http://dx.doi.org/10.1091/mbc.E10-03-0233http://dx.doi.org/10.1091/mbc.E10-03-0233http://dx.doi.org/10.1091/mbc.E10-03-0233http://dx.doi.org/10.1016/j.bbadis.2006.04.002http://dx.doi.org/10.1016/j.bbadis.2006.04.002http://dx.doi.org/10.1038/nsmb.2104http://dx.doi.org/10.1038/nsmb.2104http://dx.doi.org/10.1038/nsmb.2104http://dx.doi.org/10.1016/B978-0-12-380860-8.00005-7http://dx.doi.org/10.1038/emboj.2008.133http://dx.doi.org/10.1038/emboj.2008.133http://dx.doi.org/10.1038/emboj.2008.133http://dx.doi.org/10.1038/nrn2631http://dx.doi.org/10.1038/nrn2631http://dx.doi.org/10.1038/13001http://dx.doi.org/10.1038/13001http://dx.doi.org/10.1111/j.1399-0004.2011.01717.xhttp://dx.doi.org/10.1111/j.1399-0004.2011.01717.xhttp://dx.doi.org/10.1111/j.1399-0004.2011.01717.xhttp://dx.doi.org/10.1111/j.1399-0004.2011.01717.xhttp://dx.doi.org/10.1093/brain/aws338http://dx.doi.org/10.1093/brain/aws338http://dx.doi.org/10.1093/brain/aws338http://dx.doi.org/10.1146/annurev.neuro.31.061307.090711http://dx.doi.org/10.1146/annurev.neuro.31.061307.090711http://dx.doi.org/10.1016/j.neuron.2006.08.018http://dx.doi.org/10.1016/j.neuron.2006.08.018http://dx.doi.org/10.1016/j.neuron.2006.08.018http://dx.doi.org/10.1101/cshperspect.a001800http://dx.doi.org/10.1101/cshperspect.a001800http://dx.doi.org/10.1126/science.1226734http://dx.doi.org/10.1126/science.1226734http://dx.doi.org/10.1126/science.1226734http://dx.doi.org/10.1016/j.gep.2012.03.003http://dx.doi.org/10.1016/j.gep.2012.03.003http://dx.doi.org/10.1016/j.gep.2012.03.003http://dx.doi.org/10.1016/j.gep.2012.03.003http://dx.doi.org/10.1126/science.1215804http://dx.doi.org/10.1126/science.1215804http://dx.doi.org/10.1126/science.1215804http://dx.doi.org/10.1126/science.1152993http://dx.doi.org/10.1126/science.1152993http://dx.doi.org/10.1016/S0896-6273(02)00721-3http://dx.doi.org/10.1016/S0896-6273(02)00721-3http://dx.doi.org/10.1083/jcb.201112101http://dx.doi.org/10.1083/jcb.201112101http://dx.doi.org/10.1016/j.cell.2011.01.021http://dx.doi.org/10.1016/j.cell.2011.01.021http://dx.doi.org/10.1016/j.cell.2011.01.021http://dx.doi.org/10.1523/JNEUROSCI.0612-07.2007http://dx.doi.org/10.1523/JNEUROSCI.0612-07.2007http://dx.doi.org/10.1523/JNEUROSCI.0612-07.2007http://dx.doi.org/10.1016/j.pharmthera.2011.03.004http://dx.doi.org/10.1016/j.pharmthera.2011.03.004http://dx.doi.org/10.1038/ng.293http://dx.doi.org/10.1038/ng.293http://dx.doi.org/10.1038/ng.293http://dx.doi.org/10.1371/journal.pgen.1003066http://dx.doi.org/10.1371/journal.pgen.1003066http://dx.doi.org/10.1371/journal.pgen.1003066http://dx.doi.org/10.1371/journal.pgen.1003066http://dx.doi.org/10.1016/j.brainresbull.2012.05.003http://dx.doi.org/10.1016/j.brainresbull.2012.05.003http://dx.doi.org/10.1093/bfgp/ell002http://dx.doi.org/10.1093/bfgp/ell002http://dx.doi.org/10.1093/bfgp/ell002http://dx.doi.org/10.1016/j.conb.2008.10.003http://dx.doi.org/10.1016/j.conb.2008.10.003http://dx.doi.org/10.1001/archneur.62.1.46http://dx.doi.org/10.1001/archneur.62.1.46http://dx.doi.org/10.1016/j.cell.2013.02.031http://dx.doi.org/10.1016/j.cell.2013.02.031http://dx.doi.org/10.1126/science.1083129http://dx.doi.org/10.1126/science.1083129http://dx.doi.org/10.1126/science.1083129http://dx.doi.org/10.1126/science.1083129http://dx.doi.org/10.1371/journal.pbio.1000072http://dx.doi.org/10.1371/journal.pbio.1000072http://dx.doi.org/10.1371/journal.pbio.1000072http://dx.doi.org/10.1212/WNL.0b013e3181ec800chttp://dx.doi.org/10.1212/WNL.0b013e3181ec800chttp://dx.doi.org/10.1212/WNL.0b013e3181ec800chttp://dx.doi.org/10.1212/WNL.0b013e3181ec800chttp://dx.doi.org/10.1146/annurev.neuro.22.1.511http://dx.doi.org/10.1146/annurev.neuro.22.1.511http://dx.doi.org/10.1038/nature04736http://dx.doi.org/10.1038/nature04736http://dx.doi.org/10.1038/nature04736http://dx.doi.org/10.1126/science.1201148http://dx.doi.org/10.1126/science.1201148http://dx.doi.org/10.1126/science.1201148http://dx.doi.org/10.1126/science.1201148http://dx.doi.org/10.1016/j.cub.2010.02.058http://dx.doi.org/10.1016/j.cub.2010.02.058http://dx.doi.org/10.1016/j.cub.2010.02.058http://dx.doi.org/10.1016/j.braindev.2013.02.006http://dx.doi.org/10.1016/j.braindev.2013.02.006http://dx.doi.org/10.1016/j.braindev.2013.02.006http://dx.doi.org/10.1038/nrm2774http://dx.doi.org/10.1038/nrm2774http://dx.doi.org/10.1016/j.neuron.2010.09.039http://dx.doi.org/10.1016/j.neuron.2010.09.039http://dx.doi.org/10.1016/j.neuron.2010.09.039http://dx.doi.org/10.1016/j.ceb.2012.01.002http://dx.doi.org/10.1016/j.ceb.2012.01.002http://dx.doi.org/10.1177/1073858410386357http://dx.doi.org/10.1177/1073858410386357

Journ

alof

Cell

Scie

nce

Hoogenraad, C. C. and Bradke, F. (2009). Control of neuronal polarity andplasticity—a renaissance for microtubules? Trends Cell Biol. 19, 669-676.

Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K.,Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L. L. et al. (2010). Taumislocalization to dendritic spines mediates synaptic dysfunction independently ofneurodegeneration. Neuron 68, 1067-1081.

Hotulainen, P. and Hoogenraad, C. C. (2010). Actin in dendritic spines: connectingdynamics to function. J. Cell Biol. 189, 619-629.

Huang, C. F. and Banker, G. (2012). The translocation selectivity of the kinesins thatmediate neuronal organelle transport. Traffic 13, 549-564.

Jacobson, C., Schnapp, B. and Banker, G. A. (2006). A change in the selectivetranslocation of the Kinesin-1 motor domain marks the initial specification of theaxon. Neuron 49, 797-804.

Jaglin, X. H., Poirier, K., Saillour, Y., Buhler, E., Tian, G., Bahi-Buisson, N., Fallet-Bianco, C., Phan-Dinh-Tuy, F., Kong, X. P., Bomont, P. et al. (2009). Mutations inthe beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat. Genet.41, 746-752.

Janke, C. and Bulinski, J. C. (2011). Post-translational regulation of the microtubulecytoskeleton: mechanisms and functions. Nat. Rev. Mol. Cell Biol. 12, 773-786.

Janke, C. and Kneussel, M. (2010). Tubulin post-translational modifications: encodingfunctions on the neuronal microtubule cytoskeleton. Trends Neurosci. 33, 362-372.

Jenkins, B., Decker, H., Bentley, M., Luisi, J. and Banker, G. (2012). A novel splitkinesin assay identifies motor proteins that interact with distinct vesicle populations.J. Cell Biol. 198, 749-761.

Jolly, A. L. and Gelfand, V. I. (2011). Bidirectional intracellular transport: utility andmechanism. Biochem. Soc. Trans. 39, 1126-1130.

Kaan, H. Y., Hackney, D. D. and Kozielski, F. (2011). The structure of the kinesin-1motor-tail complex reveals the mechanism of autoinhibition. Science 333, 883-885.

Kapitein, L. C. and Hoogenraad, C. C. (2011). Which way to go? Cytoskeletalorganization and polarized transport in neurons. Mol. Cell. Neurosci. 46, 9-20.

Kapitein, L. C., Kwok, B. H., Weinger, J. S., Schmidt, C. F., Kapoor, T. M. andPeterman, E. J. (2008). Microtubule cross-linking triggers the directional motility ofkinesin-5. J. Cell Biol. 182, 421-428.

Kapitein, L. C., Schlager, M. A., Kuijpers, M., Wulf, P. S., van Spronsen, M.,

MacKintosh, F. C. and Hoogenraad, C. C. (2010a). Mixed microtubules steerdynein-driven cargo transport into dendrites. Curr. Biol. 20, 290-299.

Kapitein, L. C., Schlager, M. A., van der Zwan, W. A., Wulf, P. S., Keijzer, N. and

Hoogenraad, C. C. (2010b). Probing intracellular motor protein activity using aninducible cargo trafficking assay. Biophys. J. 99, 2143-2152.

Kardon, J. R. and Vale, R. D. (2009). Regulators of the cytoplasmic dynein motor. Nat.Rev. Mol. Cell Biol. 10, 854-865.

Kato, M. and Dobyns, W. B. (2003). Lissencephaly and the molecular basis of neuronalmigration. Hum. Mol. Genet. 12 Spec No 1, R89-R96.

Kennedy, M. B., Beale, H. C., Carlisle, H. J. and Washburn, L. R. (2005). Integrationof biochemical signalling in spines. Nat. Rev. Neurosci. 6, 423-434.

Kneussel, M. and Wagner, W. (2013). Myosin motors at neuronal synapses: drivers ofmembrane transport and actin dynamics. Nat. Rev. Neurosci. 14, 233-247.

Kon, T., Oyama, T., Shimo-Kon, R., Imamula, K., Shima, T., Sutoh, K. and Kurisu,G. (2012). The 2.8 Å crystal structure of the dynein motor domain. Nature 484, 345-350.

Konishi, Y. and Setou, M. (2009). Tubulin tyrosination navigates the kinesin-1 motordomain to axons. Nat. Neurosci. 12, 559-567.

Koushika, S. P., Schaefer, A. M., Vincent, R., Willis, J. H., Bowerman, B. and

Nonet, M. L. (2004). Mutations in Caenorhabditis elegans cytoplasmic dyneincomponents reveal specificity of neuronal retrograde cargo. J. Neurosci. 24, 3907-3916.

Kuijpers, M. and Hoogenraad, C. C. (2011). Centrosomes, microtubules and neuronaldevelopment. Mol. Cell. Neurosci. 48, 349-358.

Kull, F. J., Sablin, E. P., Lau, R., Fletterick, R. J. and Vale, R. D. (1996). Crystalstructure of the kinesin motor domain reveals a structural similarity to myosin. Nature380, 550-555.

Lai, C., Lin, X., Chandran, J., Shim, H., Yang, W. J. and Cai, H. (2007). The G59Smutation in p150(glued) causes dysfunction of dynactin in mice. J. Neurosci. 27,13982-13990.

Laird, F. M., Farah, M. H., Ackerley, S., Hoke, A., Maragakis, N., Rothstein, J. D.,

Griffin, J., Price, D. L., Martin, L. J. and Wong, P. C. (2008). Motor neurondisease occurring in a mutant dynactin mouse model is characterized by defects invesicular trafficking. J. Neurosci. 28, 1997-2005.

LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascaño, J., Tokito,

M., Van Winkle, T., Howland, D. S. and Holzbaur, E. L. (2002). Disruption ofdynein/dynactin inhibits axonal transport in motor neurons causing late-onsetprogressive degeneration. Neuron 34, 715-727.

Lee, K. H., Lee, J. S., Lee, D., Seog, D. H., Lytton, J., Ho, W. K. and Lee, S. H.

(2012). KIF21A-mediated axonal transport and selective endocytosis underlie thepolarized targeting of NCKX2. J. Neurosci. 32, 4102-4117.

Li, J., Lee, W. L. and Cooper, J. A. (2005). NudEL targets dynein to microtubule endsthrough LIS1. Nat. Cell Biol. 7, 686-690.

Li, Y., Jung, P. and Brown, A. (2012). Axonal transport of neurofilaments: a singlepopulation of intermittently moving polymers. J. Neurosci. 32, 746-758.

Lloyd, T. E., Machamer, J., O’Hara, K., Kim, J. H., Collins, S. E., Wong, M. Y.,

Sahin, B., Imlach, W., Yang, Y., Levitan, E. S. et al. (2012). The p150(Glued)CAP-Gly domain regulates initiation of retrograde transport at synaptic termini.Neuron 74, 344-360.

Lu, H., Ali, M. Y., Bookwalter, C. S., Warshaw, D. M. and Trybus, K. M. (2009).Diffusive movement of processive kinesin-1 on microtubules. Traffic 10, 1429-1438.

Lumb, J. H., Connell, J. W., Allison, R. and Reid, E. (2012). The AAA ATPasespastin links microtubule severing to membrane modelling. Biochim. Biophys. Acta1823, 192-197.

Maday, S., Wallace, K. E. and Holzbaur, E. L. (2012). Autophagosomes initiatedistally and mature during transport toward the cell soma in primary neurons. J. CellBiol. 196, 407-417.

Magariello, A., Tortorella, C., Patitucci, A., Tortelli, R., Liguori, M., Mazzei, R.,Conforti, F. L., Citrigno, L., Ungaro, C., Simone, I. L. et al. (2013). First mutationin the nuclear localization signal sequence of spastin protein identified in a patientwith hereditary spastic paraplegia. Eur. J. Neurol. 20, e22-e23.

Martin, N., Jaubert, J., Gounon, P., Salido, E., Haase, G., Szatanik, M. and Guénet,J. L. (2002). A missense mutation in Tbce causes progressive motor neuronopathy inmice. Nat. Genet. 32, 443-447.

McKenney, R. J., Vershinin, M., Kunwar, A., Vallee, R. B. and Gross, S. P. (2010).LIS1 and NudE induce a persistent dynein force-producing state. Cell 141, 304-314.

Métin, C., Vallee, R. B., Rakic, P. and Bhide, P. G. (2008). Modes and mishaps ofneuronal migration in the mammalian brain. J. Neurosci. 28, 11746-11752.

Millecamps, S. and Julien, J. P. (2013). Axonal transport deficits and neurodegenerativediseases. Nat. Rev. Neurosci. 14, 161-176.

Mitchell, D. J., Blasier, K. R., Jeffery, E. D., Ross, M. W., Pullikuth, A. K., Suo, D.,Park, J., Smiley, W. R., Lo, K. W., Shabanowitz, J. et al. (2012). Trk activation ofthe ERK1/2 kinase pathway stimulates intermediate chain phosphorylation andrecruits cytoplasmic dynein to signaling endosomes for retrograde axonal transport.J. Neurosci. 32, 15495-15510.

Mokánszki, A., Körhegyi, I., Szabó, N., Bereg, E., Gergev, G., Balogh, E., Bessenyei,B., Sümegi, A., Morris-Rosendahl, D. J., Sztriha, L. et al. (2012). Lissencephalyand band heterotopia: LIS1, TUBA1A, and DCX mutations in Hungary. J. ChildNeurol. 27, 1534-1540.

Morfini, G., Pigino, G., Mizuno, N., Kikkawa, M. and Brady, S. T. (2007). Taubinding to microtubules does not directly affect microtubule-based vesicle motility.J. Neurosci. Res. 85, 2620-2630.

Moughamian, A. J. and Holzbaur, E. L. (2012). Dynactin is required for transportinitiation from the distal axon. Neuron 74, 331-343.

Müller, M. J., Klumpp, S. and Lipowsky, R. (2008). Tug-of-war as a cooperativemechanism for bidirectional cargo transport by molecular motors. Proc. Natl. Acad.Sci. USA 105, 4609-4614.

Münch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A.,

Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G. et al. (2004). Point mutationsof the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 63, 724-726.

Nakajima, K., Yin, X., Takei, Y., Seog, D. H., Homma, N. and Hirokawa, N. (2012).Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5Adeletion causes epilepsy. Neuron 76, 945-961.

Nakata, T. and Hirokawa, N. (2003). Microtubules provide directional cues forpolarized axonal transport through interaction with kinesin motor head. J. Cell Biol.162, 1045-1055.

Nakata, T., Niwa, S., Okada, Y., Perez, F. and Hirokawa, N. (2011). Preferentialbinding of a kinesin-1 motor to GTP-tubulin-rich microtubules underlies polarizedvesicle transport. J. Cell Biol. 194, 245-255.

Namba, T., Nakamuta, S., Funahashi, Y. and Kaibuchi, K. (2011). The role ofselective transport in neuronal polarization. Dev. Neurobiol. 71, 445-457.

Nanetti, L., Baratta, S., Panzeri, M., Tomasello, C., Lovati, C., Azzollini, J., Gellera,

C., Di Bella, D., Taroni, F. and Mariotti, C. (2012). Novel and recurrent spastinmutations in a large series of SPG4 Italian families. Neurosci. Lett. 528, 42-45.

Newsway, V., Fish, M., Rohrer, J. D., Majounie, E., Williams, N., Hack, M.,Warren, J. D. and Morris, H. R. (2010). Perry syndrome due to the DCTN1 G71Rmutation: a distinctive levodopa responsive disorder with behavioral syndrome,vertical gaze palsy, and respiratory failure. Mov. Disord. 25, 767-770.

Niwa, S., Nakajima, K., Miki, H., Minato, Y., Wang, D. and Hirokawa, N. (2012).KIF19A is a microtubule-depolymerizing kinesin for ciliary length control. Dev. Cell23, 1167-1175.

Niwa, S., Takahashi, H. and Hirokawa, N. (2013). b-Tubulin mutations that causesevere neuropathies disrupt axonal transport. EMBO J.

Ori-McKenney, K. M., Xu, J., Gross, S. P. and Vallee, R. B. (2010). A cytoplasmicdynein tail mutation impairs motor processivity. Nat. Cell Biol. 12, 1228-1234.

Ou, C. Y., Poon, V. Y., Maeder, C. I., Watanabe, S., Lehrman, E. K., Fu, A. K.,

Park, M., Fu, W. Y., Jorgensen, E. M., Ip, N. Y. et al. (2010). Two cyclin-dependent kinase pathways are essential for polarized trafficking of presynapticcomponents. Cell 141, 846-858.

Pandey, J. P. and Smith, D. S. (2011). A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axons. J. Neurosci. 31, 17207-17219.

Perlson, E., Maday, S., Fu, M. M., Moughamian, A. J. and Holzbaur, E. L. (2010).Retrograde axonal transport: pathways to cell death? Trends Neurosci. 33, 335-344.

Pfister, K. K., Shah, P. R., Hummerich, H., Russ, A., Cotton, J., Annuar, A. A.,

King, S. M. and Fisher, E. M. (2006). Genetic analysis of the cytoplasmic dyneinsubunit families. PLoS Genet. 2, e1.

Pilling, A. D., Horiuchi, D., Lively, C. M. and Saxton, W. M. (2006). Kinesin-1 andDynein are the primary motors for fast transport of mitochondria in Drosophila motoraxons. Mol. Biol. Cell 17, 2057-2068.

Poirier, K., Saillour, Y., Bahi-Buisson, N., Jaglin, X. H., Fallet-Bianco, C., Nabbout,R., Castelnau-Ptakhine, L., Roubertie, A., Attie-Bitach, T., Desguerre, I. et al.

(2010). Mutations in the neuronal b-tubulin subunit TUBB3 result in malformation of


http://dx.doi.org/10.1016/j.tcb.2009.08.006http://dx.doi.org/10.1016/j.tcb.2009.08.006http://dx.doi.org/10.1016/j.neuron.2010.11.030http://dx.doi.org/10.1016/j.neuron.2010.11.030http://dx.doi.org/10.1016/j.neuron.2010.11.030http://dx.doi.org/10.1016/j.neuron.2010.11.030http://dx.doi.org/10.1083/jcb.201003008http://dx.doi.org/10.1083/jcb.201003008http://dx.doi.org/10.1111/j.1600-0854.2011.01325.xhttp://dx.doi.org/10.1111/j.1600-0854.2011.01325.xhttp://dx.doi.org/10.1016/j.neuron.2006.02.005http://dx.doi.org/10.1016/j.neuron.2006.02.005http://dx.doi.org/10.1016/j.neuron.2006.02.005http://dx.doi.org/10.1038/ng.380http://dx.doi.org/10.1038/ng.380http://dx.doi.org/10.1038/ng.380http://dx.doi.org/10.1038/ng.380http://dx.doi.org/10.1038/nrm3227http://dx.doi.org/10.1038/nrm3227http://dx.doi.org/10.1016/j.tins.2010.05.001http://dx.doi.org/10.1016/j.tins.2010.05.001http://dx.doi.org/10.1083/jcb.201205070http://dx.doi.org/10.1083/jcb.201205070http://dx.doi.org/10.1083/jcb.201205070http://dx.doi.org/10.1042/BST0391126http://dx.doi.org/10.1042/BST0391126http://dx.doi.org/10.1126/science.1204824http://dx.doi.org/10.1126/science.1204824http://dx.doi.org/10.1016/j.mcn.2010.08.015http://dx.doi.org/10.1016/j.mcn.2010.08.015http://dx.doi.org/10.1083/jcb.200801145http://dx.doi.org/10.1083/jcb.200801145http://dx.doi.org/10.1083/jcb.200801145http://dx.doi.org/10.1016/j.cub.2009.12.052http://dx.doi.org/10.1016/j.cub.2009.12.052http://dx.doi.org/10.1016/j.cub.2009.12.052http://dx.doi.org/10.1016/j.bpj.2010.07.055http://dx.doi.org/10.1016/j.bpj.2010.07.055http://dx.doi.org/10.1016/j.bpj.2010.07.055http://dx.doi.org/10.1038/nrm2804http://dx.doi.org/10.1038/nrm2804http://dx.doi.org/10.1093/hmg/ddg086http://dx.doi.org/10.1093/hmg/ddg086http://dx.doi.org/10.1038/nrn1685http://dx.doi.org/10.1038/nrn1685http://dx.doi.org/10.1038/nrn3445http://dx.doi.org/10.1038/nrn3445http://dx.doi.org/10.1038/nature10955http://dx.doi.org/10.1038/nature10955http://dx.doi.org/10.1038/nature10955http://dx.doi.org/10.1038/nn.2314http://dx.doi.org/10.1038/nn.2314http://dx.doi.org/10.1523/JNEUROSCI.5039-03.2004http://dx.doi.org/10.1523/JNEUROSCI.5039-03.2004http://dx.doi.org/10.1523/JNEUROSCI.5039-03.2004http://dx.doi.org/10.1523/JNEUROSCI.5039-03.2004http://dx.doi.org/10.1016/j.mcn.2011.05.004http://dx.doi.org/10.1016/j.mcn.2011.05.004http://dx.doi.org/10.1038/380550a0http://dx.doi.org/10.1038/380550a0http://dx.doi.org/10.1038/380550a0http://dx.doi.org/10.1523/JNEUROSCI.4226-07.2007http://dx.doi.org/10.1523/JNEUROSCI.4226-07.2007http://dx.doi.org/10.1523/JNEUROSCI.4226-07.2007http://dx.doi.org/10.1523/JNEUROSCI.4231-07.2008http://dx.doi.org/10.1523/JNEUROSCI.4231-07.2008http://dx.doi.org/10.1523/JNEUROSCI.4231-07.2008http://dx.doi.org/10.1523/JNEUROSCI.4231-07.2008http://dx.doi.org/10.1016/S0896-6273(02)00696-7http://dx.doi.org/10.1016/S0896-6273(02)00696-7http://dx.doi.org/10.1016/S0896-6273(02)00696-7http://dx.doi.org/10.1016/S0896-6273(02)00696-7http://dx.doi.org/10.1523/JNEUROSCI.6331-11.2012http://dx.doi.org/10.1523/JNEUROSCI.6331-11.2012http://dx.doi.org/10.1523/JNEUROSCI.6331-11.2012http://dx.doi.org/10.1038/ncb1273http://dx.doi.org/10.1038/ncb1273http://dx.doi.org/10.1523/JNEUROSCI.4926-11.2012http://dx.doi.org/10.1523/JNEUROSCI.4926-11.2012http://dx.doi.org/10.1016/j.neuron.2012.02.026http://dx.doi.org/10.1016/j.neuron.2012.02.026http://dx.doi.org/10.1016/j.neuron.2012.02.026http://dx.doi.org/10.1016/j.neuron.2012.02.026http://dx.doi.org/10.1111/j.1600-0854.2009.00964.xhttp://dx.doi.org/10.1111/j.1600-0854.2009.00964.xhttp://dx.doi.org/10.1016/j.bbamcr.2011.08.010http://dx.doi.org/10.1016/j.bbamcr.2011.08.010http://dx.doi.org/10.1016/j.bbamcr.2011.08.010http://dx.doi.org/10.1083/jcb.201106120http://dx.doi.org/10.1083/jcb.201106120http://dx.doi.org/10.1083/jcb.201106120http://dx.doi.org/10.1111/ene.12000http://dx.doi.org/10.1111/ene.12000http://dx.doi.org/10.1111/ene.12000http://dx.doi.org/10.1111/ene.12000http://dx.doi.org/10.1038/ng1016http://dx.doi.org/10.1038/ng1016http://dx.doi.org/10.1038/ng1016http://dx.doi.org/10.1016/j.cell.2010.02.035http://dx.doi.org/10.1016/j.cell.2010.02.035http://dx.doi.org/10.1523/JNEUROSCI.3860-08.2008http://dx.doi.org/10.1523/JNEUROSCI.3860-08.2008http://dx.doi.org/10.1038/nrn3380http://dx.doi.org/10.1038/nrn3380http://dx.doi.org/10.1523/JNEUROSCI.5599-11.2012http://dx.doi.org/10.1523/JNEUROSCI.5599-11.2012http://dx.doi.org/10.1523/JNEUROSCI.5599-11.2012http://dx.doi.org/10.1523/JNEUROSCI.5599-11.2012http://dx.doi.org/10.1523/JNEUROSCI.5599-11.2012http://dx.doi.org/10.1177/0883073811436326http://dx.doi.org/10.1177/0883073811436326http://dx.doi.org/10.1177/0883073811436326http://dx.doi.org/10.1177/0883073811436326http://dx.doi.org/10.1002/jnr.21154http://dx.doi.org/10.1002/jnr.21154http://dx.doi.org/10.1002/jnr.21154http://dx.doi.org/10.1016/j.neuron.2012.02.025http://dx.doi.org/10.1016/j.neuron.2012.02.025http://dx.doi.org/10.1073/pnas.0706825105http://dx.doi.org/10.1073/pnas.0706825105http://dx.doi.org/10.1073/pnas.0706825105http://dx.doi.org/10.1212/01.WNL.0000134608.83927.B1http://dx.doi.org/10.1212/01.WNL.0000134608.83927.B1http://dx.doi.org/10.1212/01.WNL.0000134608.83927.B1http://dx.doi.org/10.1016/j.neuron.2012.10.012http://dx.doi.org/10.1016/j.neuron.2012.10.012http://dx.doi.org/10.1016/j.neuron.2012.10.012http://dx.doi.org/10.1083/jcb.200302175http://dx.doi.org/10.1083/jcb.200302175http://dx.doi.org/10.1083/jcb.200302175http://dx

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