artigo 19- the propagation of prion-like protein inclusions in neurodegenerative diseases

8/6/2019 Artigo 19- The Propagation of Prion-like Protein Inclusions in Neurodegenerative Diseases

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The propagation of prion-like proteininclusions in neurodegenerative

diseasesMichel Goedert1, Florence Clavaguera2 and Markus Tolnay2

1 MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK2 University of Basel, Institute of Pathology, Scho ¨ nbeinstrasse 40, 4031 Basel, Switzerland

The most common neurodegenerative diseases, in-

cluding Alzheimer’s disease and Parkinson’s disease,

are characterized by the misfolding of a small number

of proteins that assemble into ordered aggregates in

affected brain cells. For many years, the events leading

to aggregate formation were believed to be entirely cell-

autonomous, with protein misfolding occurring inde-

pendently in many cells.Recent research has now shown

that cell non-autonomous mechanisms are also import-

ant for the pathogenesis of neurodegenerative diseases

with intracellular filamentous inclusions. The intercellu-

lar transfer of inclusions made of tau, a-synuclein, hun-

tingtin and superoxide dismutase 1 has been

demonstrated, revealing the existence of mechanisms

reminiscent of those by which prions spread through the

nervous system.

Prions

The prion concept [1] continues to influence the under-

standing of neurodegeneration. Prions are infectiousproteins whose ability to propagate results from their

b-sheet-rich conformation converting the prion protein to

the aberrant form through a process of nucleated polymer-

ization. They cause the invariably fatal transmissible

spongiform encephalopathies (TSEs), also known as prion

diseases (Table 1). These diseases include Kuru, Creutz-

feldt–Jakob disease, Gerstmann–Straussler–Scheinker

disease (GSS) and fatal familial insomnia in man, bovine

spongiform encephalopathy (BSE) in cattle and scrapie in

sheep.

Prion diseases are sporadic, inherited or infectious and

rely on the conversion of the normal cellular form of the

prion protein, PrPC, to a misfolded form, PrPSc. Cases of

familial prion disease cosegregate with germline

mutations in the prion protein gene [2]. PrPSc can assemble

into several structurally distinct conformers or strains,

giving rise to distinct disease traits, incubation periods,

rates of progression and pathologies [3].

Prion-like aggregates have also been identified in fungi,

where proteins unrelated to the prion protein, such as

Ure2, Sup35, Rnq1 and HET-s, replicate through a mech-

anism of self-propagating conformation [4]. Each protein

assembles into filaments that are infectious through their

ability to grow by recruiting the soluble form of the protein.

Filament fragmentation is important for replication

because a reduction in filament length, also known as

secondary nucleation, enhances filament load through seed

extension. This could also be true of mammalian prions, for

which an inverse correlation between aggregate stability

and incubation times of disease has been demonstrated [5].

Neurodegenerative diseases that involve protein

misfolding

Prion diseases belong to the group of protein misfolding

neurodegenerative diseases that are characterized by the

abnormal aggregation of defined host proteins. The mis-

folded proteins form highly ordered filamentous

inclusions with a core region of cross-b-conformation.

Tau, b-amyloid and a-synuclein are the most commonly

misfolded proteins [6]. Whereas prion diseases are rare,

Alzheimer’s disease (AD), Parkinson’s disease (PD) and

frontotemporal dementia (FTD) are common. Like most

cases of prion disease, they are largely sporadic, with a

small percentage being inherited (Table 1). Mutations inthe genes encoding amyloid precursor protein (APP), tau

and a-synuclein cause dominantly inherited forms of AD,

FTD and PD [7–12]. Mutations in superoxide dismutase 1

(SOD1), TAR DNA-binding protein 43 (TDP-43) and fused

in sarcoma (FUS) cause familial forms of amyotrophic

lateral sclerosis (ALS) [13–16]. Some cases of inherited

FTD are also caused by mutations in TDP-43 (Table 1).

Huntington’s disease (HD), which is caused by mutations

in huntingtin [17], and other polyglutamine diseases, are

always inherited.

An important difference between TSEs and other mis-

folding diseases is that prions behave like infectious

agents. They can be transmitted between individualsand across species, giving rise to epidemics, such as Kuru

and BSE. In addition, prions can spread from the point of

infection, often a peripheral tissue, to the central nervous

system (CNS), where they cause devastating neurodegen-

eration [3]. The ability to transfer between cells is a central

property of prions.

Current evidence suggests that common misfolding dis-

eases are not transmitted between individuals. However,

investigation of the formation of tau and a-synuclein

inclusions as a function of age has shown that they develop

in a stereotypical manner in particular brain regions from

where they appear to spread [18,19] (Figure 1). This is

consistent with an intercellular transfer of inclusions,

Review

Corresponding author: Goedert, M. ([email protected] ).

0166-2236/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2010.04.003 Trends in Neurosciences 33 (2010) 317–325 317

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provided one accepts that studies of their temporal appear-ance describe a single pathophysiological process.

The relationship between TSEs and other neurodegen-

erative diseases has been studied for many years [20–23].

However, it is the flurry of recent research describing the

induction of protein misfolding and spreading between

cells [24–38] that has shown most convincingly that com-

mon neurodegenerative diseases can be driven by cell non-

autonomous mechanisms. Research has indicated that

characteristics of misfolded prion protein can be shared

by other proteins central to neurodegenerative diseases.

Proteins exhibiting prion-like properties have also been

named ‘prionoids’ [35,36].

Tau protein

The microtubule-associated protein tau is the most com-

monly misfolded protein in human neurodegenerative dis-

eases. These diseases include AD, some cases of GSS,

familial British and Danish dementias, Pick’s disease, pro-

gressive supranuclear palsy (PSP), corticobasal degener-ation (CBD), argyrophilic grain disease (AGD), Guam

Parkinsonism-dementia complex, tangle-only dementia,

white matter tauopathy with globular glial inclusions and

frontotemporal dementia and Parkinsonism linked to

chromosome 17 (FTDP-17T) [6] (Table 1). In these diseases,

the normally soluble tau protein is hyperphosphorylated

and filamentous. Whereas the hyperphosphorylated sites in

tau are similar between diseases, filament morphologies

vary widely [39].

Intraneuronal tau inclusions coexist with extracellular

deposits of b-amyloid in AD, prion protein in some forms of

GSS and BRI2 in British and Danish dementias. However,

Table 1. Protein misfolding neurodegenerative diseases

Misfolded protein Human disease Familial

cases

Prion protein Kuru À

Creutzfeldt-Jakob disease +/ À

Gerstmann–Stra ¨ ussler– +

Scheinker disease

Fa tal famili al i nsomnia +/ À

b-Amyloid Alzheimer’s disease +/ À

BRI2 British dementia +Danish dementia +

Tau Alzheimer’s disease À

Gerstmann–Stra ¨ ussler– À

Scheinker disease

British dementia À

Danish dementia À

Pick’s disease +/ À

Progressive supranuclear

palsy

+/ À

Corticobasal degeneration +/ À

Argyrophilic grain disease +/ À

Guam Parkinsonism-

dementia complex

À

Tangle-only dementia À

White matter tauopathy

with globular glialinclusions

À

Frontotemporal dementia

and Parkinsonism linked

to chromosome 17

+

a-Synuclein Parkinson’s disease +/ À

Dementia with Lewy

bodies

+/ À

Multiple system atrophy À

Pure autonomic failure À

Lewy body dysphagia À

Superoxide dismutase 1 Amyotrophic lateral

sclerosis

+/ À

TAR DNA-binding

protein 43

Amyotrophic lateral

sclerosis

+/ À

Frontotemporaldementia

+/ À

Fused in sarcoma Amyotrophic lateral

sclerosis

+/ À

Frontotemporal

dementia

À

Huntingtin Huntington’s disease +

Symbols: ‘‘+’’ indicates that the disease is inherited and caused by dominant

mutations in the gene encoding the misfolded protein or multiplications of the

gene, ‘‘+/ –’’indicates that thediseaseis inherited insomecasesandcaused bysuch

mutations or multiplications and ‘‘À’’ indicates that known cases of the disease are

not caused by dominant mutations in the gene encoding the misfolded protein or

multiplications of the gene.

Figure 1. Temporospatial spreading of tau-positive neurofibrillary lesions in the

process of Alzheimer’s disease (left, green) and a-synuclein-positive lesions (Lewy

bodies and neurites) in the process of Parkinson’s disease and dementia with Lewy

bodies (right, red). (Left) According to Braak and Braak [18], six stages (I–VI) of tau

pathology can be distinguished. Stages I–II show alterations that are largely

confined to the upper layers of the transentorhinal cortex (transentorhinal stages).

Stages III–IV are characterized by a severe involvement of the transentorhinal and

entorhinal regions, with a less severe involvement of the hippocampus and several

subcortical nuclei (limbic stages). Stages V–VI show the massive development of

neurofibrillary pathology in neocortical association areas (isocortical stages) and a

further increase in pathology in the brain regions affected during stages I–IV. The

shading intensities of the areas colored in green are proportional to the severity of

tau pathology. Adapted, with permission, from Ref. [18]. (Right) According to

Braak et al. [19,83], six stages (I–VI) of a-synuclein pathology can be distinguished.

The first lesions appear in the olfactory bulb, the anterior olfactory nucleus and the

dorsal motor nucleus of the vagus and glossopharyngeal nerves in the medulla

oblongata (stages I and II). From the brainstem, the inclusions take an ascending

path to the lower raphe nuclei, the gigantocellular reticular nucleus and the locus

coeruleus (indicated by white arrows). In stages III and IV, they reach the

amygdala, the cholinergic nuclei of the basal forebrain and the substantia nigra.

The cerebral cortex also becomes affected starting with the anteromedial temporal

mesocortex. In stages V and VI, the inclusions spread to the higher order sensory

association and prefrontal areas, the first order sensory association areas, the

premotor area and the primary sensory and motor fields. The shading intensities

of the areas colored in red are proportional to the severity of a-synuclein

pathology. Adapted, with permission, from Ref. [83].

Review Trends in Neurosciences Vol.33 No.7

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there are diseases, such as PSP, CBD, AGD, Pick’s disease,

Guam Parkinsonism-dementia complex, tangle-only

dementia, white matter tauopathy with globular glial

inclusions and FTDP-17T, which are characterized by

the presence of tau inclusions in the absence of extracellu-

lar deposits. Whereas most of these diseases are sporadic,

FTDP-17T is caused by mutations in Tau, establishing

that dysfunction of tau is sufficient to cause neurodegen-

eration and dementia [6,10–

12].Genetic variation in Tau also plays a role in sporadic

diseases. Thus, inheritance of the Tau H1 haplotype is a

risk factor for PSP and CBD [40–42]. Haplotypes H1 and

H2 result from a 900-kb inversion polymorphism that

encompasses the tau gene [43]. Heterozygous microdele-

tions of this region give rise to a clinical syndrome of

mental retardation, hypotonia and facial dysmorphism

[44–46], consistent with the notion that tauopathies are

caused by a gain of toxic function of tau.

The formation of tau inclusions thus appears to be

essential for causing neurodegeneration. From the above,

it is clear that multiple factors can trigger their formation.

What is less clear is whether, as it develops, tau pathology becomes self-sustaining and why it is characteristic of so

many diseases.

In adult human brain, six tau isoforms are expressed

from a single gene through alternative mRNA splicing [47]

(Figure 2). The microtubule-binding repeats form the core of

the tau filamentswhose isoform composition varies between

diseases [6]. The assembly of four-repeat tau into filaments

is characteristicof PSP, CBD, AGD,white matter tauopathy

with globular glial inclusions and many cases of FTDP-17T.

A combination of neuronal and glial tau pathology is pre-

sent, with the glial pathology predominating in white mat-

ter tauopathy with globular glial inclusions [48]. By

contrast, in Pick’s disease and some cases of FTDP-17T,

three-repeat tau predominates in the neuronal inclusions,

whereas in AD, other diseases with extracellular deposits,

Guam Parkinsonism-dementia complex, tangle-only

dementia and some cases of FTDP-17T, both three- and

four-repeat tau make up the neurofibrillary lesions.

Filamentous inclusions made of all six tau isoforms form

in a stereotypical manner during aging. This underlies the

‘‘Braak stages’’ of tau pathology, which range from stages I

toVI [18] (Figure 1). Stages I and II are thought to correlatewith preclinical AD, stages III and IV with mild cognitive

impairment and stages V – VI with AD. It suggests that the

process leading to full-blown AD begins in the transen-

torhinal cortex, where the first cells in the brain to develop

neurofibrillary lesions are located, from where it spreads to

the hippocampal formation and the neocortex. Many tau

inclusions survive the death of the affected nerve cells as

extracellular or ghost tangles.

Stereotypical spatial and temporal spreading of tau

inclusions has also been noted in AGD, a four-repeat

tauopathy [49,50]. The earliest changes are restricted to

the ambient gyrus (stage I), from where the pathological

process extends to the anterior and posterior medialtemporal lobe (stage II), followed by the septum, insular

cortex and anterior cingulate gyrus (stage III). Stage III is

characteristic of patients with a clinical diagnosis of

dementia.

These findings are consistent with an intercellular

transfer of tau aggregates. The presence of inclusions made

of distinct sets of tau isoforms in different diseases is

consistent with the existence of tau strains, akin to the

prion strains made of distinct conformers of PrPSc.

Although suggestive, these findings are merely correla-

tional and lack direct experimental support. This has

changed over the past year, with the description of the

intercellular transfer of tau aggregates, both in vivo and in

vitro [29,30]. Thus, the injection of sonicated brain extract

from mice transgenic for human mutant P301S tau

(Figure 3a) into the cerebral cortex and hippocampus of

mice transgenic for human wild-type tau (Figure 3b)

induced the assembly of wild-type human tau into fila-

ments (Figure 3c) and led to the spreading of pathology

from the sites of injection to neighboring brain regions [29].

The induction of filamentous tau was time- and brain

region-dependent and included the formation of neurofi-

brillary tangles, neuropil threads and oligodendroglial

coiled bodies. When brain extract from human P301S

tau mice was injected into control mice, neuropil threads

and coiled bodies formed at the injection sites.

Injection of brain extract immunodepleted of tau(Figure 3d) or divided into soluble and insoluble fractions

showed that insoluble tau induced aggregation. The

absence of obvious signs of neurodegeneration following

the injection of brain extract came as a surprise and stands

in marked contrast to the extensive nerve cell loss that

characterizes the P301S tau parent line [51]. At a mini-

mum, this suggests that the tau species responsible for

transmission and toxicity are not identical. It remains to be

seen how this relates to the relevance of current transgenic

mouse models of tauopathy, which often exhibit massive

neurodegeneration in the absence of abundant inclusions

[52], for an understanding of human tauopathies.

Figure 2. Schematic representation of the human tau gene and the six tau

isoforms expressed in adult brain. The human tau gene consists of 16 exons (E).

Alternative splicing of E2 (red), E3 (green) and E10 (yellow) gives rise to the six tau

isoforms (352–441 amino acids). The constitutively spliced exons (E1, E4, E5, E7,

E9, E11, E12, E13) are indicated in blue. E0, which is part of the promoter, and E14

are non-coding (white). E6 and E8 (violet) are not transcribed in human brain. E4a

(orange) is only expressed in the peripheral nervous system. Black bars indicate

the microtubule-binding repeats of tau, with three isoforms having four repeats

each (4R hTau) and three isoforms having three repeats each (3R hTau). Each

repeat is 31 or 32 amino acids in length. Similar levels of 4R and 3R tau isoforms

are expressed in normal human brain. The exons and introns are not drawn to

scale.


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Parallel work has demonstrated the transfer of tau

inclusions between transfected non-neuronal cells [30]

and the templated transmission of the conformational

properties of assembled recombinant tau [53]. Filaments

made in vitro from the microtubule-binding domain of four-

repeat human tau were taken up into cells by fluid-phase

endocytosis, where they induced filament formation of full-

length tau, probably following direct contact through a

prion-like mechanism. The likely relevance of these find-

ings is underscored by the fact that in human tauopathies,

especially AD, tau inclusions outlast the death of affectednerve cells and accumulate in the extracellular space.

This research has demonstrated that tau aggregates can

propagate a misfolded state to the inside of cells and has

provided an experimental system by which to identify the

molecular mechanisms underlying the intercellular trans-

fer of inclusions. The behavior of misfolded tau is reminis-

cent of that of protease-resistant prion protein and the

yeast prion Sup35NM [54,55].

b-Amyloid

Unlike inclusions made of tau, a-synuclein, huntingtin and

SOD1, b-amyloid deposits form in the extracellular space.

Several years ago, it was shown that the injection of brain

extract from AD patients into the brain of mice transgenic

for human mutant APP promotes the aggregation and

deposition of b-amyloid [24]. The mice developed amyloid

deposits earlier and in larger amounts than vehicle-injected

littermates. Similar findings were subsequently reported

following the intracerebralinjection of b-amyloid-containing

brain extract from transgenic mouse lines APP23 and

APPPS1 [27]. APP23 mice mainly overproducethe 40-amino

acid peptide of b-amyloid, which results in the deposition of

diffuse and filamentous deposits with age. APPPS1 miceoverproduce the 42-amino acid peptide of b-amyloid and

developcompact,punctatedeposits.Injectionofbrainextract

fromaged APPPS1mice intoyoung APP23 hosts inducedthe

formation of punctateb-amyloid deposits, whereas injection

of brain extract from APP23 mice into APP23 hosts gave

rise to diffuse and filamentous deposits. Injection of brain

extract from APP23 mice into young APPPS1 hosts resulted

in a mixture of filamentous and punctate b-amyloid

deposits, whereas injection of APPPS1 brain extract into

APPPS1-expressing mice resulted in punctate staining.

These findings areconsistent withearlier studiessuggesting

the existence of polymorphic strains of b-amyloid [56,57].

Figure 3. Induction of filamentous tau pathology in the brain of transgenic ALZ17 mice expressing human wild-type tau following the injection of brain extract from mice

transgenic for human mutant P301S tau. (a) Mice expressing the 383 amino acid four-repeat isoform of human tau (4R hTau) with the P301S mutation under the control of

the murine Thy1 promoter develop abundant Gallyas–Braak silver-positive filamentous tau inclusions and widespread nerve cell loss, including in the brainstem, the brain

region used for preparation of the extract injected in parts (c) and (d). The silver-positive tau inclusions are immunoreactive with antibody AT8, a marker for

hyperphosphorylated tau. In humans, the P301S mutation causes an aggressive form of FTDP-17T [109]. (b) In contrast, mice expressing the 441 amino acid 4R hTau

isoform under the control of the murine Thy1 promoter (line ALZ17) do not develop Gallyas –Braak silver-positive inclusions (right inset) or nerve cell loss, even though

human tau is hyperphosphorylated at the AT8 epitope (left inset), as shown for the hippocampus. Hyperphosphorylation (detected by AT8) precedes the assembly of tau

into filaments (detected by Gallyas–Braak silver). The mechanistic connections between hyperphosphorylation and aggregation of tau, two invariant features of human

tauopathies, remain to be fully elucidated. (c) The injection of brain extract from P301S tau transgenic mice into the hippocampus and the cerebral cortex of ALZ17 mice

induces the formation of Gallyas–Braak silver-positive inclusions made of filamentous, hyperphosphorylated wild-type human tau [29]. Hippocampal dentate gyrus from an

ALZ17 mouse is shown 15 months after the injection of brainstem extract from a 6-month-old P301S mouse. Silver-positive neurofibrillary tangles, neuropil threads andoligodendroglial coiled bodies are in evidence. (d) Injection of the same extract as in part (c), but immunodepleted of tau, shows no Gallyas–Braak silver-positive inclusions

15 months later. Scale bar, 50 mm.


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b-Amyloid deposits appeared to spread from the sites of

injection to more distant brain regions. Immunodepletion or

formic acid treatment abolished the amyloid-promoting

activity of the extract, indicating that the active agent

consisted of aggregated species of b-amyloid. However,

synthetic filaments of b-amyloid failed to promote amyloid

deposition. Administration of brain extract through an oral,

intravenous, intraocular or intranasal route did not lead to

cerebral b-amyloidosis, in contrast to the experimentaltransmission of prion diseases [31]. In cultured nerve

cells, b-amyloid is taken up and concentrated in endo-

somes/lysosomes [34]. Vesicular b-amyloid can aggregate

and is capable of seeding the growth of amyloid filaments

inside cells. It remains to be seen whether filaments can be

released and seed the formation of extracellular plaques.

The injection of brain extract from aged b-amyloid-

depositing APP23 mice into the brains of mice transgenic

for human mutant P301L tau markedly potentiated the

formation of silver-positive tau inclusions [58], in line with

previous research on double transgenic mouse lines [59]. A

similar effect was observed following the injection of syn-

thetic b-amyloid filaments into the brains of mice trans-genic for human mutant P301L tau [60], indicating that

the molecular species which promote the formation of tau

inclusions and b-amyloid aggregates are not identical.

These findings have demonstrated the existence of mech-

anisms by which aggregated b-amyloid can cause the

hyperphosphorylation and aggregation of human mutant

tau. However, the relevance of studies using mutant APP

and mutant tau for AD remains to be clarified, because b-

amyloid fails to induce tau aggregation in mouse lines

transgenic for human wild-type tau [61].

a-Synuclein

a-Synuclein is the major component of the largely neuronal

filamentous inclusions that make up Lewy bodies and

Lewy neurites, the defining neuropathological character-

istics of PD, dementia with Lewy bodies (DLB) and several

rarer conditions including pure autonomic failure and

Lewy body dysphagia [62,63] (Table 1). a-Synuclein is also

the major component of Papp–Lantos inclusions, the

mainly oligodendroglial filamentous inclusions that are

diagnostic of multiple system atrophy (MSA) [64,65]. Fila-

ment morphologies differ between Lewy body diseases and

MSA, indicating that distinct conformers of assembled a-

synuclein can give rise to different neurodegenerative

diseases. They also differ between wild-type and mutant

a-synuclein, further suggesting the existence of different

strains [66].Whereas most cases of Lewy body disease and MSA are

sporadic, rare familial forms of PD and DLB are caused by

missense mutations in the a-synuclein gene or multipli-

cations of the gene [9,67]. Furthermore, sequence variation

in the a-synuclein gene is a risk factor for sporadic PD and

MSA [68–71]. More unexpected was the finding that the H1

haplotype of Tau is also a risk factor for PD [70–72].

Missense mutations in the a-synuclein gene and overpro-

duction of wild-type a-synuclein are believed to cause

disease through a gain of toxic function, implying that

the formation of a-synuclein inclusions is essential for

causing neurodegeneration.

a-Synuclein is an abundant brain protein of 140 amino

acids that binds lipids through its amino-terminal repeat

region [73–75]. It also assembles through this region,

which forms the core of the disease filaments [76].

Although its physiological function is unknown, a-synu-

clein is believed to play a role in the assembly of the protein

complexes required for chemical neurotransmission [77].

Incidental Lewy body disease describes the presence of

small numbers of Lewy bodies and neurites in the absenceof clinical symptoms [78]. It is observed in 5–10% of the

general population over the age of 60 years and may

represent a preclinical form of Lewy body disease. Anec-

dotal evidence has suggested that a prodromal form of

MSA could also exist [79]. In cases with incidental Lewy

body disease, the first a-synuclein-positive structures in

the brain form in the dorsal motor nucleus of the glosso-

pharyngeal and vagus nerves, the olfactory bulb and the

anterior olfactory nucleus [19]. The inclusions then ascend

rostrally from the brainstem to the midbrain and cerebral

cortex (Figure 1), contradicting the long-held view that PD

begins in the nigrostriatal system and is limited to the

degeneration of dopaminergic nerve cells of the substantianigra. Recent research is consistent with the presence of

non-motor signs in PD, including hyposmia, sleep depri-

vation and sensory symptoms [80].

a-Synuclein deposits appear to form even earlier in the

enteric and peripheral nervous systems, suggesting that

Lewy body diseases could originate outside the CNS

[81,82]. This view underlies a staging scheme, which pro-

poses that pathological inclusions progress from enteric

and autonomic nervous systems to the brainstem and

higher parts of the neuraxis [83]. It suggests that environ-

mental factors could gain access to the enteric nervous

system, where they induce the aggregation of a-synuclein.

This would be analogous to the transmission and spread-

ing of prion disease following the ingestion of BSE-infected

meat [84]. A recent study has shown that intragastric

administration of the pesticide rotenone resulted in the

formation of pathological forms of a-synuclein in the

enteric nervous system, the dorsal motor nucleus of the

vagus nerve and the substantia nigra of wild-type mice

[85].

This raises the possibility that a-synuclein pathology

could spread between synaptically connected neurons. In

support, studies of the brains of PD patients who had

received fetal mesencephalic nerve cell transplants 11–

16 years earlier revealed the presence of Lewy bodies in

the grafts [86–88] (Figure 4). These findings are consistent

with a spread of seeds from the diseased host tissues to thegrafts, followed by the nucleated polymerization of a-synu-

clein. In the grafts, up to 5% of dopaminergic neurons

contained Lewy bodies [89], similar to the proportion of

Lewy body-bearing neurons (3.6%) in the substantia nigra

of patients with PD [90]. It has been suggested that nerve

cells with Lewy bodies die within 6 months of inclusion

formation and that the generation of Lewy bodies and

nerve cell death reaches a steady state [90]. According to

this model, a-synuclein inclusions cause nerve cell death.

Experimental support for the existence of cell-to-cell

transfer of a-synuclein inclusions has come from research

showing that misfolded intraneuronal a-synuclein can


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transfer to neighboring cells both in culture and in trans-

genic mice [32]. This was associated with pathological

changes and signs of neurodegeneration in acceptor cells.

It had previously been reported that a small amount of a-

synuclein is intravesicular and secreted [91]. A separate

study has provided evidence for the nucleated polymeriz-ation of a-synuclein in transfected cells but failed to

observe efficient cell-to-cell transfer of the misfolded

protein [33]. This discrepancy between the two studies

could reflect the fact that the intercellular transfer of

misfolded seeds of a-synuclein is a relatively rare event.

Other proteins forming intracellular inclusions

Assessing the temporospatial spreading of inclusions

requires hundreds of brains with different amounts of

pathology. This has only been achieved for inclusions made

of tau protein and a-synuclein [18,19]. For a-synuclein, it

has been shown that the accumulation of internalized

misfolded protein increases when lysosomal function is

reduced, with little effect of proteasomal inhibition [32].

Reduced lysosomal activity of acceptor cells could therefore

be partially responsible for the accumulation of misfolded

a-synuclein. Proteins endocytosed and trafficked in this

manner will be inside vesicles, with soluble tau and a-

synuclein being cytoplasmic. Nucleated polymerization

therefore requires the penetration of the cytoplasmic com-

partment by filamentous aggregates. The presence in the

cytoplasm of aggregates following their uptake into cells

has been demonstrated most clearly for filaments made

from peptides of polyglutamine in the pathological range

[28].

Several years ago, it was shown that polyglutamine

aggregates are readily taken up by cells, where they exhi-bit marked cytotoxicity upon nuclear translocation [25].

Recent research has shown that polyglutamine aggregates

can gain access to the cytoplasmic compartment, where

they nucleate the assembly of a soluble, amino-terminal

fragment of huntingtin [28].

Dominantly inherited mutations in SOD1 cause ALS,

which is characterized by the formation of filamentous

inclusions made of the mutant protein [13] (Table 1).

Multiple lines of evidence indicate that the mechanisms

underlying nerve cell death in the human disease and

animal models thereof are cell non-autonomous [92]. Inter-

estingly, mutant, but not wild-type SOD1, interacts with

chromogranins A and B, leading to its secretion [26].

Extracellular mutant SOD1 has been reported to activate

microglia, resulting in the degeneration of motor neurons

[36]. These findings have suggested that toxicity of mutant

SOD1 requires activation of the innate immune system.

The relevance of this work could be more general, as it hasbeen reported that a variant in chromogranin B (P413L) is

a risk factor for sporadic ALS [93].

It remains to be seen whether mammalian cells can

mount a defense response to eliminate cytosolic protein

aggregates, similar to what happens when bacterial patho-

gens escape into the nutrient-rich cytosol. Bacteria are

eliminated by mechanisms involving ubiquitination and

clearance by autophagy [94], reminiscent of studies which

have shown that the pharmacological or genetic induction

of autophagy delays the onset of model AD, PD, HD, ALS

and prion disease [95,96].

Mechanistic implications

It seems likely that prion-like aggregates are released

from cells and taken up by neighboring cells, where

they penetrate the cytoplasm and nucleate further

aggregation (Figure 5). The full significance of recent

findings will only become clear when the underlying

mechanisms are better understood. It has been reported

that prions transfer between cultured cells through

exosomes and tunneling nanotubes (TNTs) [97,98].

Alternatively, the spread of prions could be mediated

by the conversion of PrPC on the surface of one cell to

PrpSc by contact with another cell bearing PrpSc on its

surface [99]. However, the latter mechanism is unlikely

to be relevant for cytoplasmic proteins, such as tau,

a-synuclein, huntingtin and SOD1.Exosomes are small vesicles of endocytic origin that are

released by most cells [100] (Figure 5a). They participate in

the transport of proteins, lipids and RNA. Exosomes form

intracellularly by the inward budding of early endosomes,

resulting in the formation of multivesicular bodies (MVBs).

The latter fuse with the plasma membrane, releasing the

exosomes into the extracellular space. Following their

release, exosomes can be endocytosed by neighboring cells.

The endocytic pathway can be coupled to autophagy. It has

been reported that autophagy promotes the fusion of MVBs

with autophagic vacuoles and blocks exosome secretion,

suggesting a possible link between the cellular reaction to

Figure 4. Host-to-graft spreading of Lewy body pathology in a patient with Parkinson’s disease. This patient received a transplant of fetal human mesencephalic

dopaminergic neurons into the putamen 16 years previously. Immunohistochemistry for a-synuclein visualizes Lewy bodies and Lewy neurites in (a) the host substantia

nigra and (b, c) the transplant. Scale bars, 40 mm. Adapted, with permission, from Ref. [86].


322



cytoplasmic aggregates and intercellular aggregate trans-

fer [101]. b-Amyloid has been shown to be secreted via

exosomes [102]. The amyloidogenic processing of APP by b-

and g-secretases generates b-amyloid in early endosomes,

which are then trafficked to MVBs. It remains to be seen

whether aggregates of tau, a-synuclein, huntingtin and

SOD1 can shuttle between cells via exosomes.In addition to exosomes, TNTs have been reported to

play a role in the intercellular spread of prions [98]. They

are believed to provide the predominant route for the

transfer of prions between immune cells and neurons.

TNTs are F-actin-containing membranous channels that

connect cells over long distances and traffic proteins and

organelles [103] (Figure 5b). Their relevance, if any, for the

intercellular spread of prion-like aggregates remains to be

established.

The internalization of aggregates and the subsequent

nucleated polymerization of cytosolic proteins in target

cells is perhaps the most mysterious aspect of the inter-

cellular transfer of prion-like aggregates. If the aggregates

are internalized through endosomes, the vesicular con-

tents of endosomes could be released into the cytoplasm

of target cells through fusion with the plasma membrane or

the endosomal membrane (Figure 5a). Mechanisms could

also exist that allow aggregates to diffuse across the endo-

somal membrane into the cytoplasm (Figure 5b). The latter

is reminiscent of how some toxins and viruses gain access

to the cytoplasm [104,105].

Concluding remarks

Until recently, the most common neurodegenerative dis-

eases were believed to develop in a cell-autonomous man-

ner, which implies that abnormal protein aggregates form

independently in affected brain cells. It is easy to see how

this can happen in inherited cases of disease, where the

aggregating protein is either mutant or overproduced. It is

more difficult to envisage a similar process occurring in

sporadic cases of disease, where the aggregating protein is

wild-type and its expression is unchanged. Recent studies

have suggested that cell non-autonomous mechanisms

could play a more important role than hitherto suspected,emphasizing the relevance of ongoing immunotherapeutic

approaches [106–108]. The processes underlying sporadic

cases of disease could originate in a highly localized man-

ner (i.e. a single cell), from where they spread to remote

brain areas through intercellular transfer. These findings

are likely to influence thinking about the most common

neurodegenerative diseases and open the way to the

development of novel therapeutic strategies.

AcknowledgementsM.G. is supported in part by the UK Medical Research Council and the

Alzheimer’s Research Trust. F.C. and M.T. are supported by the Swiss

National Science Foundation.

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