Huntington’s Disease: Voluntary Movement and the Mechanisms for Failure A Comprehensive Manual For the Instructor and Student Dakota Binkley, Eva Clark-Lepard, Jaime Knoch, and Angelico Obille  

 

 

 

 

 

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Table of Contents: Instructor’s Manual……………………..…………………………………………………....3

Teaching Overview……............................................................................................................3

Logistics…………………………………………………………………………………………..5

Worksheets...............................………………………………………………………………….6

Unit Content………………………………………………………………...………………......18

Section 1: Brain Anatomy and Voluntary Movement………………………………...……......18

Section 2: Basal Ganglia and the Direct and Indirect Pathways for Voluntary Movement….....20

Section 3: Neurotransmitters in Movement………...……...……………………...……..….. 22

Section 4: Genetic Predisposition in Huntington’s Disease…………...……...…..……….......26

Section 5: Cognitive and Psychological Effects of Huntington’s Disease and Prognosis...…......30

Supplementary Reading List…………………………………………………………………...35

Glossary………………………………………………………………………………………….39

Student’s Manual………………...…………………………………………………………..43

Introduction……………………………………………………………………………………..43

Instructions For Students…………………………………………….......................................47

Supplementary Reading List…………………………………………………………………...49

Accompanying Material…………………………….……………………………………...51

Full Bibliography………………………………………………………………………………..51

Contributions……………………………………………………………………………………59

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Instructor's Manual (5893): Teaching Overview (492) Rationale

The purpose of this unit is to expose students to interdisciplinary learning within medical

sciences. This unit is designed to introduce several fundamental concepts of neuroscience. These

concepts include basic brain anatomy, the function of nerves cell synapses, and neurotransmitter

transmission and reception. They will also learn about the process of protein gene encoding and

possible mutations that can occur, as well as psychological effects and potential treatments of

neurological disorders. This unit will be taught through the example of Huntington’s disease (HD)

since teaching through example enhances student understanding of concepts (Brown, 1992).

To teach this unit, the neuroscience concepts and basics of HD should be explained to the

class in a classic lecture style. It is under the discretion of the instructor to decide the amount of

detail of HD applied to the neuroscience content. Activities are strongly recommended to be

completed by the class. These activities are designed to substantiate student-learning experience.

Instructions regarding how to conduct each activity can be found in "Worksheets".

Assessments

The students will be assessed in various ways, including: a unit test, activities, participation,

class discussion topics, and homework assignments (Table T.1). Students will be expected to write a

unit test after the 5 chapters are completed to demonstrate a full understanding of the unit content.

They will also be expected to actively participate in class discussions. It is suggested that a discussion

is hosted in each lecture to ensure that students are constantly aware various topics of HD. Activity

1 will be marked for participation and contributions. Research take-home questions on a topic are to

be assigned for extra credit, for students to explore HD further. Research topics may include:

exploring Parkinson’s disease, other common neurotransmitters, or mental health treatments. These

topics will not be covered in detail in class, allowing students to gain primary research experience.

Finally, three additional worksheet-style activities based on the unit content sections will be assigned.

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Table T.1: The various assessments suggested while teaching this

unit and their appropriate weighting.

Assessments Amount % Worth

Activities 4 30

Participation 1 10

Class discussion of topics 1 15

Research take home question 1 15

Unit test 1 30

There are different activities associated with each chapter (Table T.2). Each activity should

be introduced while the associated chapter in being taught. The activities for chapters 4 and 5 can be

considered take home assignments.

Table T.2: Lecture days and the corresponding activities for each chapter.

Lecture Topic In-Class Activity Due

1 Brain Anatomy and Voluntary Movement Circuits in the Brain N/A

2 The Basal Ganglia and the Direct and

Indirect Pathways for Voluntary Movement

N/A Next

class

3 Neurotransmitters in Movement Investigations of Voluntary

Movement

Next

class

4 Genetics Predisposition of HD HD Diagnosis and Prognosis –

Part 1: Genetics

Next

class

5 Cognitive and Physiological Effects of HD

& Prognosis

HD Diagnosis and Prognosis –

Part 2: Clinical Symptoms

Day of

Unit Test

 

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Logistics (173)

This teaching unit is for a high school grade 12 university biology class. Disciplines covered

in this unit include biology, biochemistry, chemical biology, and psychology, and all of these

concepts are covered in the context of neuroscience. Students should consider both grade 10 general

science and grade 11 biology as prerequisites. In these courses, basic cell biology and genetics should

have been covered since students will require prior knowledge in these areas. The major concepts

covered in this unit are brain anatomy, movement pathways (voluntary and involuntary), genetics,

protein transcription and folding, and cognitive and psychological effects of neurodegenerative

diseases. All concepts will be taught through the example of HD. Approximately 10 minutes are

required to set up computers and print activity sheets. This is the only setup needed for the unit.

This unit should be taught in a basic classroom setting, preferably with seating allowing students to

interact in groups. A projector, printed activities, and a chalk/white board are necessary for teaching

purposes and therefore should be present in the classroom of choice.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Worksheets (1891)

Activity 1: Nervous Circuits in Movement - A Brain Anatomy Activity Instructions:

1. Split class in half, form two parallel lines facing each other.

2. Explain to students that the first two people in each line will be the sensory input and the upper motor neurons. One of these two will start the pulse when given the signal by the instructor.

3. The second X amount of students in the line are local circuit neurons, the third X amount are lower motor neurons, and the person at the end of each line is the muscle cell.

4. Tell the students that they are competing against the other line of students to see which group can stimulate the muscle cell first.

5. Tell the students to close their eyes and tell them that you will tap either the sensory input or the upper motor neurons on each line and that is the queue for them to send a pulse.

6. As soon as the last person in each line feels the pulse they reach for some (non dangerous) object in between them, first person to grab it stimulates the muscle cell!

Figure A.1.1: A sample set-up of one of the two lines.

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Activity 2: Pathways of Voluntary Movement

This activity is designed to develop a deeper understanding of the circuitry within the basal

ganglia (Section 2) and the neurotransmitters involved in these pathways (Section 3). The students

will be given a blank template (Figure A.2.1) with all the structures involved in the direct and

indirect pathways of the basal ganglia. The task is to follow the procedure listed in this document

and complete the template. Throughout the activity, the student will fill in information regarding the

excitatory/inhibitory circuitry, the direction of the synapses, and the neurotransmitters involved.

Figure A.2.1: A blank template listing all the structures involved in

voluntary movement.

Task 1: Excitatory or inhibitory? (Section 2)

The first task is to identify whether the interaction between nuclei are excitatory or inhibitory.

If they are excitatory, the activity of the post-synaptic nucleus is increased; if they are inhibitory, the

activity of the post-synaptic nucleus is decreased. Connect lines between each nucleus with a red

marker to indicate an excitatory interaction. Connect lines between each nucleus with a blue marker

to indicate an inhibitory interaction.

Task 2: Which direction? (Section 2)

The second task is to outline the direction of the interactions between nuclei. Recall that the

structures do not follow a linear order of synapses, i.e. some interactions may be reciprocal and

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some interactions may go backwards. Use arrowheads to indicate the direction of the synapses from

the pre-synaptic nucleus to the post-synaptic nucleus.

Task 3: Glutamate, dopamine, and GABA? (Section 3)

The third task is to identify which neurotransmitter is secreted by the nuclei to complete the

synaptic interactions. Recall that the three neurotransmitters involved in the basal ganglia are

glutamate, dopamine, and GABA. Use a legend to label each structure as either glutamatergic,

dopaminergic, or GABAergic.

Task 4: How does it lead to movement?

The final task is to follow the direct and indirect pathways of movement and determine

whether or not the activity of the next structure is increased or decreased, beginning with the cortex

exciting the neostriatum. Draw arrows beside the structures to indicate the type of activity. An arrow

up represents that the activity of that structure is increased. An arrow down represents that the

activity of that structure is decreased. Conclude whether an increase or decrease in cortex activity

results in movement.

Figure A.2.2: A template listing the structures involved in the indirect and

direct pathways.

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Answer Key:

Task 1:

Task 2:

Task 3:

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Task 4:

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Activity 3: HD Diagnosis and Prognosis – Part 1: Genetics

The iSci Medical Research Team requires your assistance in determining who (out of the

following 4 individuals) could be diagnosed with EOHD or HD in their lifetime (Figure A.3.1).

Through a series of simple genetic tests and profiling your team must determine whom this disease

will affect and why. First look at the different profiles to get an understanding about their genetic

history.

Figure A.3.1: A schematic diagram showing each individual being tested for HD. The information presented shows family history of the disease, the individuals’ name, gender and age. You must keep this information in mind while analyzing the genetic data presented.

Secondly, you need to determine who has genetic traits that could lead to HD using the

information outlined in Table A.3.1.

Table A.3.1: A table presenting simplified genetic information of HD for each individual. Determine the

alleles of each person’s parents (determining dominant and receive). This assignment assumes that those

with the receive allele do not carry any mutation. Note: for this answer key, H is dominant and h is recessive.

Individual of Interest Mother Father Allele of Mother Allele of Father

Anna No history of HD No history of HD hh

hh

Katie Strong history of

HD

No history of HD HH

unknown

Ben No history of HD Slight history of HD hh hH

Josh No history of HD No history of HD hh hh

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1. Whose parents are heterozygote receives and dominants?

2. Whose parents are homozygotes? Please answer in Table A.3.2.

Note: you can assume that Katie’s father is homozygote receive

Table A.3.2: A table organizing your answers to questions 1 and 2.

Individual of Interest Mother Father

Anna Homozygote receive Homozygote receive

Katie Homozygote dominant Homozygote receive

Ben Homozygote receive Heterozygote

Josh Homozygote receive Homozygote receive

Thirdly, you must complete Punnet squares to determine the likelihood of each individual

developing HD. Please use the tables outlined in Figure A.3.2.

Figure A.3.2: Four Punnet squares with simplified genetic information regarding each individual’s family history. Students are required to determine the likelihood of each individual being diagnosed with HD based on the information presented in Table A.3.1 and their answers to Table A.3.2.

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Each individual had his or her DNA tested for the HD repeat (CAG). Their DNA was run

on a gel electrophoresis. This is a common biochemical technique that can be used to determine

certain cut sits of restriction enzymes and determine the length of certain sections of DNA. The iSci

Medical Research team has already completed this and have removed all plasmid drop out fragments

so you can focus on the length of the CAG repeats found in the DNA. Analyze the image provided

in Figure A.3.3 and complete Table A.3.3.

Figure A.3.3: An image of an agarose gel that shows the amount of basepairs of CAG each individual has in their DNA. The ladder is measured in basepairs. You are required to record this information and deduce who is most likely to have EHOD, have HD, who is at risk, and who is not at risk.

Table A.3.3: A table where to place analysis of Figure A.3.4.

Anna Katie Ben Josh

Basepair length 90 450 150 60

Repeat length 30 150 50 20

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Now that you have obtained all of he genetic information required to make a diagnosis you

can accurately determine who will have EOHD, HD or no HD. Complete Table A.4.4 with all

relevant information.

Table A.3.4: A table used to collect all of the information and make a final diagnosis

Anna Katie Ben Josh

Family History None Heavy Slight None

Punnet Square 100% not likely 100% likely 50% likely 100% not likely

Gel

electrophoresis

30 repeats

found

150 repeats

found

50 repeats

found

20 repeats

found

Final diagnosis At risk EOHD HD once older Never will be

diagnosed with

HD

Follow up Questions:

1. Why were you allowed to assume that Katie’s father was a homozygous receive (hh) for HD?

• You only need one dominate parent that carries the gene for one to show symptoms and

develop the large repeat

2. Does gender matter when determining the likelihood of HD? Why or why not?

• Various theories are present but no one gender has been shown to be more prominent than

another

• The disorder is on chromosome 4, which is not a sex chromosome

3. How do physicians usually test for HD?

• Through neurological evaluations of movement and development

• Gene testing, using basic genetics and blood samples from the person under investigation

and his or her family members (United States Huntington’s Disease Genetic Testing Group,

2003)

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Activity 4: HD Diagnosis and Prognosis – Part 1: Clinical Symptoms

Now that you know that Katie will suffer from EOHD and Ben will suffer from HD, you

can now determine the most likely symptoms they will develop over time, treatments used and other

problems they may encounter. Use the words provided in the word bank (Figure A.4.1) to complete

Table A.4.1.

Figure A.4.1: A word bank of potential symptoms Katie and Ben might face. Please choose who is most likely to develop what symptoms and put your answers in Table A.4.1. Hint: Not all answers in the word bank need to be used and Katie and Ben can have the same symptoms

Table A.4.1: A table to match items from Figure A.4.1 to Katie and/or Ben.

Katie Ben

Seizures Chorea

Memory dysfunction Memory dysfunction

Changes in personality Changes in personality

Symptoms of chorea Anxiety, depression and reduced mental

flexibility.

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Bradyphrenia Bradyphrenia

Anxiety, depression and reduced mental

flexibility. Suicide rate 5-10%

OCD Life expectancy of 15-20 years after symptom

onset

Suicide rate 23% Use of SSRIs

Life expectancy of less than 15 years after

symptom onset

Use of atypical neuroleptics

Use of SSRIs

Use of anticonvulsants

Use of atypical neuroleptics

To understand HD, it is important to understand depression since it is a prevalent issue with

HD patients. You have to understand both the issue of depression and how it can be treated.

Additionally, you must understand the side effects of various treatments. Use the following word

bank found in Figure A.4.2 to complete the following fill in the blanks.

Figure 5.4.2: The word bank used to fill in the blanks regarding information about depression. Hint: Not all words are used, some word maybe used twice.

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Commonly those who suffer from depression and have HD face suicide ideation during two

periods of HD. The monoamine hypothesis of depression was developed to help understand why

depression occurs in those who are and are not suffering from HD. Decreased levels of monoamine

neurotransmitters such as dopamine and norepinephrine have been found in brains of suicide

victims. Successful treatments of antidepressants have managed to increased monoamine

neurotransmitters in the CNS. A lot of antidepressants also focus on blocking SERT with SSRIs to

reduce the symptoms of depression.

Follow up Questions

1. How do Katie and Ben use atypical neuroleptics?

Katie uses atypical neuroleptics to manage her symptoms of chorea and symptoms of OCD,

while Ben uses atypical neuroleptics to manage his symptoms of chorea and anxiety.

2. Why does is Katie’s life expectancy different than Ben’s?

EOHD progresses faster than HD, so she has a shorter life expectancy.

3. What symptoms are the anticonvulsants used to treat?

Katie uses anticonvulsants to manage her seizures.

4. What is bradyphrenia?

Bradyphrenia describes slow thinking.

5. Why do EOHD and HD have a higher suicide rate then the general population?

EOHD and HD have higher suicide rates due to prevalent neurobehavioural disorders such

as anxiety, depression and obsessive-compulsive disorders. These disorders are coupled with

symptoms of low mood, lower self-esteem, hopelessness and loss of interest, which are

associated with suicide ideation.

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Unit Content (3781) Section 1: Brain Anatomy in Voluntary Movement (531)

The circuitry involving movement is mainly as a result of sensory/voluntary inputs to the

local circuitry, signalling lower motor neurons to move the muscles. The local circuitry is signalled

directly by either sensory inputs or upper motor neurons. Sensory inputs include reactions to

tactile, visual or auditory inputs, while the upper motor neurons compose the descending systems

that involve the motor cortex and the brainstem center structures. The motor cortex is specifically

in charge of planning, initiating, and directing voluntary movements, and the brainstem centers are

in charge of basic movements and postural control. The motor cortex and brainstem centers

together form the descending modulating systems that are regulated by the cerebellum and the basal

ganglia (Figure 1.1) (Purves et al. 2008).

Figure 1.1: A schematic showing the general overview of the

circuitry involved in the movement of skeletal muscles (Adapted from Purves et al. 2008).

Before understanding how voluntary movement is compromised by HD, voluntary

movement under regular conditions must first be understood. The focus here is on the workings of

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the descending systems associated with the upper motor neurons in the motor cortex. The

connection between the nervous system and the musculoskeletal system is reliant on the connection

between the local circuitry and the skeletal muscles (Purves et al. 2008). The interaction between

these two organ systems ultimately results in movement.

The cerebellum regulates the signals transmitted by the brainstem centres by assessing the

differences between performed movements and intended movements. In a way, the cerebellum acts

as a calibration system for movement. The basal ganglia are of particular interest in this unit since

they are in charge of gating proper initiation of movement. The basal ganglia operate via two

pathways: the direct pathway, which stimulates the initiation of movement, and the indirect

pathway, which inhibits the initiation of movement (Kandel et al. 2008).

Defects in the two pathways involved in the basal ganglia lead to disorders in muscle control

such as Parkinson’s disease (PD) and HD (Kandel et al. 2008). In particular, PD is associated with

defects in the direct pathway. A defect in the direct pathway causes disabilities in initiating

movement, resulting in slow movement responses and other symptoms, as seen in PD. In contrast,

HD is predominantly associated with defects in the indirect pathway. A defect in the indirect

pathway causes disabilities in stopping movement once initiated, which results in chorea, a

characteristic symptom of HD (Ross & Tabrizi 2011).

Voluntary movement is initiated by the primary motor

cortex, which is composed of upper motor neurons that

directly stimulate the local circuit neurons that in turn

stimulate the lower motor neurons, resulting in the

movement of muscles. The signals from the primary motor

cortex are regulated by the thalamus, which acts as a

connection between sensory inputs and the primary motor

cortex. The basal ganglia refer to a complex of nuclei that

regulate the signals of the thalamus, which will influence the

signals to the primary motor cortex and the control of

movement (Figure 1.2) (Nicholls et al. 2012).

Patients suffering from degenerative diseases such as

HD, PD, and motor neuron disease develop the ongoing atrophy of various structures in the

nervous system. HD patients exhibit considerable brain volume reduction in the overall cortex and

also in the striatum, a subcortical nucleus within the basal ganglia (Halliday et al. 1998).

Figure 1.2: A summary of the circuitry of the descending systems of motor control (Adapted from Atrain CEU n.d.).

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Section 2: Basal Ganglia and the Direct and Indirect Pathways for Voluntary Movement (347)

The basal ganglia are regulatory structures in the brain that gate proper initiation of

movement by adjusting the excitatory activity of the thalamus (Purves et al., 2008). The basal ganglia

do this via the direct pathway, which increases thalamic activity, and the indirect pathway, which

inhibits thalamic activity. Movement is initiated or inhibited by stimuli from the primary motor

cortex. The thalamus excites or inhibits the PMC. Therefore, the basal ganglia indirectly control and

mitigate movement control.

There are three main components in the basal ganglian mechanisms: the direct pathway, the

indirect pathway, and the regulatory pathways. In the direct pathway, the Primary Motor Cortex

(PMC) excites the neostriatum, causing the inhibition of the globus pallidus internus (GPi). The

GPi is normally an inhibitory nucleus that inhibits the thalamus. The inhibition of the GPi causes

the excitation of the thalamus, which causes an increase in PMC activity and initiates movement.

Although the excitation of the PMC is important, the inhibition of the primary motor cortex

is equally important to motor control. The globus pallidus externus (GPe) and the subthalamic

nucleus (STN) are involved in the indirect pathway. In the indirect pathway, the PMC excites the

neostriatum, which causes the inhibition of GPe. This relieves the inhibition of STN, which causes

an increased activity of the GPi. Increasing activity of the GPi causes more inhibition of the

thalamus, which suppresses activation of the PMC, ultimately suppressing movement.

  Figure 2.1: The circuitry between the nuclei within the basal ganglia. The red

connections represent excitatory neurons, and blue connections represent inhibitory neurons.

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The basal ganglia contain the substantia nigra, a regulatory structure that is important in

mediating the interactions between the direct and indirect pathways (Figure 2.1). The substantia

nigra receives inputs from the PMC, signaling that a movement will begin. It then stimulates the

direct pathway and inhibits the indirect pathway (Kandel et al. 2008). The substantia nigra can be

divided into two sections, the pars nigra compacta (SNc) and the pars nigra reticulata (SNr). SNc

provides the neostriatum with dopamine to produce net excitation of the striatum (Nicholls et al.

2012). SNr works in conjunction with the GPi in inhibiting the thalamus and further supports the

direct and indirect pathways (Figure 2.2).

 

Figure 2.2: The direct and indirect pathways. An increase in cortical activity results in the initiation of movement; a decrease in cortical activity results in the inhibition of movement.

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Section 3: Neurotransmitters in Movement (989)

Neurotransmitters, along with many other aspects of the brain, facilitate the generation of

movement. The three main neurotransmitters involved in the synapses within the basal ganglia

pathways are gamma-aminobutyric acid (GABA), dopamine, and glutamate. GABA is an inhibitory

neurotransmitter while dopamine and glutamate are excitatory neurotransmitters (Nicholls et al.

2012). These three neurotransmitters are active throughout the brain; however each

neurotransmitter is more prevalent in certain areas of the brain (Figure 3.1).

Figure 3.1: A schematic diagram of the circuitry around the basal ganglia including the neurotransmitters associated with the synapses. The red arrows show excitatory pathways and the blue arrows show inhibitory pathways.

Gamma-aminobutyric acid (GABA)

HD damage is most evident in the striatum as it is characterized by striatal neuron loss

(Chen et al. 2013). Over 90% of striatal neurons are GABAergic projection medium-sized spiny

neurons (MSNs) (Chen et al. 2013). Defects in the MSNs or the neurotransmitters and their

receptors result in significant implications in both the indirect and direct pathways of voluntary

movement. This is because they are involved in every synaptic interaction (Chen et al. 2013;

Gepshtein et al. 2014).

GABA functions as an inhibitory neurotransmitter within the main connections in the basal

ganglia circuit (i.e. neostriatum to the globus pallidus and globus pallidus to the thalamus). GABA-

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gated ion channels are permeable to chloride and bicarbonate ions. GABA inhibits neurons by

increasing the chloride and bicarbonate conductance. This occurs because of the activation of

GABA-A receptors. When GABA-A channels open, they hyperpolarize the cell, increasing the

threshold potential. As such, the cell is less likely to reach the threshold potential required to fire

an action potential, and this inhibits the neuron (Roth, Draguhn 2012) (Figure 3.2).

Figure 3.2: A basic depiction of neurotransmitters and the GABA receptor. A receptor is a protein within the membrane (with some extracellular portions) that is activated by certain neurotransmitters. The two types of GABA receptors are: GABA-A receptors, which are ligand-gated, and GABA-B receptors, which are G-protein coupled (Dutar & Nicoll 1988). Neurotransmitters, such as GABA are released from the postsynaptic neuron into the synapse (the gap between the pre and postsynaptic neurons). Receptors are embedded on the ends of the postsynaptic neuron. Once neurotransmitters bind to the receptor it is activated. In the context of HD, this activation results in uncontrollable movement (Chen et al. 2013). Figure source: (Clapp et al. n.d.)

Dopamine

Dopamine functions as an excitatory neurotransmitter between the subthalamic nucleus pars

compacta (SNc) and the neostriatum. This stimulates the activity of the neostriatum to allow it to

follow the direct pathway. Imbalances in dopamine levels or destruction of dopaminergic neurons

and their receptors can decrease the patient’s ability to perform voluntary actions. Current research

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indicates that this is the cause of the long-term decrease of voluntary movements (hypokinesia) seen

in patients with HD (Gepshtein et al. 2014).

Glutamate

Glutamate is an excitatory neurotransmitter found in the connections between the cortex

and the neostriatum and between the subthalamic nucleus and the GPi (Nicholls et al. 2012).

Impairment of glutamate uptake has been found to contribute to HD as it slows down the excitatory

activity against the GPi. This decceleration leads to less inhibition on the thalamus, creating

excessive movements characteristic of HD (Andre et al. 2011).

The Dysfunction of Neurotransmitters and their Receptors

Dopamine and GABA are two of the most prominent neurotransmitters associated with HD

and other related neurodegenerative diseases. This is because of the significance of the synaptic

connections facilitated by these neurotransmitters to motor control (Chen et al. 2013).

GABA directly inhibits both the direct and the indirect pathways of the basal ganglia,

meaning that the loss of GABAergic neurons or receptors in the striatum that are intrinsic to HD

can cause hyperactivity of these pathways. This hyperactivity causes chorea associated with the

dysfunction of the indirect pathway and the gradual decline of motor skills (Gepshtein et al. 2014).

In the early stages of HD, there is also a loss of dopamine availability in the caudate nucleus,

putamen, and GPe (Glass et al. 2000). Additionally GABA-A receptors increase binding activity in

the GPe. As the disease progresses, these symptoms increase, causing GABA-A receptors increase

function, which also contributes to uncontrollable movement. The degeneration of GABAergic

striatal projection neurons is correlated with increasing stage of the disease.

It is well established that changes in the availability of striatal dopamine and its receptors

affect cognitive function and can lead to the symptoms of HD (Chen et al. 2013). Dopamine

reduces the function of the indirect pathway and increases function of the direct pathway in the

basal ganglia. It has been experimentally determined that increased striatal dopamine levels induce

chorea, and decreased striatal dopamine levels lead to the reduced ability to generate voluntary

movements (Chen et al. 2013). It has been proposed that dopamine enables voluntary movement by

providing causation for action. As such, the loss of dopaminergic neurons or receptors would cause

the decrease in the ability to perform voluntary motor movements (Gepshtein et al. 2014).

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Similarly to GABA receptors, dopaminergic neurons and receptors can also be substantially

degraded in the onset of HD. Specifically, dopaminergic neurons of the substantia nigra are highly

vulnerable to damage, and when enough of these neurons are damaged, hypokinesia can develop.

It is mainly associated with PD, and it is the main distinguishing factor between PD and HD. HD is

mainly associated with hyperkinesia, which is the increase in muscular movement. Hyperkinesia

results in the characteristic chorea as a later onset symptom (Gepshtein et al. 2014).

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Section 4: Genetic Disposition in Huntington’s Disease (992)

HD is an autosomal dominant disease caused by a trinucleotide repeat of CAG (the codon

for glutamine). This repeat is found at the 5’ end of the interesting transcript gene 15 located on

chromosome 4, which codes for Huntingtin protein (Htt) (Sakazume et al. 2009; Nahhas et al. 2009;

Buttar et al. 2002). The average human has between 11 and 29 repeats, while those who are affected

by HD have this repeat anywhere between 39 and 112 times (Goh 2011). Individuals with 30-38

repeats are considered at risk for HD development. These CAG repeats are commonly referred to as

poly-Q repeats. The onset of HD is inversely proportional to the amount of CAG repeats an

individual has. For instance, patients with greater than 100 repeats will experience symptoms at a

younger age than those with 45 repeats (Nahhas et al. 2009).

This mutation can be inherited both maternally and paternally (Sakazume et al. 2009). Those

who have anywhere from 36-39 repeats generally do not show symptoms however their offspring

can be diagnosed with HD if they inherit the pathogenic allele. Mutant alleles can be inherited

from the father even if he does not show symptoms and is never diagnosed with HD (Roze et al.

2010). However, it is understood that there is a direct relationship between the father and the

daughter in the onset of HD. Additionally, it has been shown that those who suffer from Early-

Onset Huntington's Disease (EOHD) usually receive the mutated gene from their father, while

those who have a later onset tend to receive the mutation from their mother. Heterozygosity for the

expanded CAG allele causes the disease phenotype while homozygosity also causes disease

phenotype (Yamamoto et al. 2000).

The non-pathogenic allele expands into the pathogenic allele through a process known as

reverse slippage. This causes the gene to code for a protein with a larger poly-Q tract, such as

Mutant Htt (Figure 4.1) (Baranov et al. 2005). Reverse slippage is more likely to occur during

spermatogenesis compared to oogenesis, which is why the disease is more likely to arise de novo

paternally (McMurry 2010). Slippage occurs during transcription when the template strand is being

replicated (Baranov et al. 2005). Reverse slippage adds more nucleotide bases to a protein sequence

than were initially coded for (Figure 4.1). Usually, this occurs multiple times within the normal poly-

Q region of Htt, causing the allele to possess more CAG repeats and become the pathogenic type.

The function of the normal Htt protein is unknown however it does not interact with

essential cellular functions. Current research suggests that mutant Htt can bind to HAP-1 protein

within cells (Wu & Zhou 2009). The HAP-1 protein is mainly expressed in the brain. The unnatural

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Figure 4.1: An illustration of how slippage can occur during transcription. In the top image, normal transcription is shown. In the second image, reverse slippage is shown. Reverse slippage can cause a short genetic sequence to be repeated during transcription (Baranov et al. 2005). During transcription RNA polymerase disconnects from the DNA, and upon reattachment it attaches to the incorrect position and recopies the same section. Figure source: (“Repetitious DNA” n.d.)

binding to this protein can cause a decrease in the trafficking of vesicles and important organelles

such as the mitochondria, which can be detrimental to cellular function. Secondly, the protein can

negatively interact with histones in the cell, which can inhibit proper protein folding and function

(Sadri-Vakili & Cha 2006). This occurs because histones function to allow for efficient packing of

DNA. Histones work to compact the strands of DNA when the DNA is not in a state of

transcription (Freeman 2008). Once transcription occurs, the histone’s hold weakens the strength of

the DNA, which allows RNA polymerase easy access to the DNA for transcription. In the context

of HD, the mutant Htt attaches to the histones and inhibits transcription (Sadri-Vakili & Cha 2006),

which can have detrimental effects within cells since proper proteins are not transcribed resulting in

dysfunction.

Aggregates of the protein also cause dysfunction in the cell due to their toxicity (Nahhas et

al. 2009; Cattaneo et al. 2001), and their tendency to decrease the kinase activity in cells resulting in

autophagy. Aggregates are the insoluble granules of Htt that are found in the cellular compartment

of neurons. The N-terminals of the insoluble aggregates accumulate in axon terminals and the

nucleolus (Cattaneo et al. 2001). The soluble form of Htt interacts with synaptic vessels resulting in

the inhibition of glutamate uptake. Once enough soluble and insoluble aggregates enter the cells, the

  28

basal ganglia become dysfunctional, culminating in the symptoms of HD (Nahhas et al. 2009). These

granules of Htt can also directly affect neural conductivity (Savas et al. 2010). Normally, mRNA

translation transport is regulated in neurons since mRNA is required for synaptic strength. Usually,

neural granules transport the mRNA along microtubules and control some protein synthesis in

dendrites. Htt can interact with these regulatory transport systems to create a neurotoxin that also

leads to dysfunction. Aggregates are usually found in or directly outside the nucleus. However, the

mutant Htt can interact with the mitochondria, cytosol, and the process of transcription as well

(Ross & Tabrizi 2011; Landles & Bates 2004).

Usually, chaperone proteins inhibit the production of aggregates, however, this ineffective

against Htt aggregates (Landles Bates 2004; Lodish et al. 2013). Hsp70 and its homologs are major

chaperones in all animal cells. They function as a part of a cellular cycle that contributes to

proteostasis (Figure 4.2) (Hartl et al. 2011; Lodish et al. 2013). This cycle does not function

Figure 4.2: A schematic diagram of the Hsp70 cycle that controls protein folding to reduce aggregates formed in animal cells. Once nascent peptides – also known as unfolded peptides – are detected they bind to the open conformation of the substrate-binding domain (SBD) (shown in orange) of the Hsp70 (1). The ATP present is transformed to ADP by the other proteins within the cell (DnaJ and Hsp40), which triggers a conformational change of the Hsp70 where the unfolded protein is trapped in the SBD (2). An ATP exchange occurs which opens the Hsp70 back to its initial conformation, with the assistance of GrpE and BAG1 (3). The properly formed peptides are then released (4). Image source and information obtained from: (Lodish et al. 2013).

  29

properly when a cell has the mutant misfolded Htt protein. Chaperones also assist in autophagy,

known as chaperone-mediated autophagy (CMA) where the cell can selectively degrade cytosolic

proteins in the lysosomes (Kaushik & Cuervo 2008). If this pathway is impaired due to stress from

toxins or oxidative stress, the chance of mutant proteins such as Htt surviving in the cell increases

greatly. Hsp70 recognizes the mutated protein and mediates its presence through CMA. Hsp70

binds to the mutated protein and transports it to the surface of the lysosomes where a protein

associated with the lysosome (LAMP-2A), acts as a receptor for CMA. Once the mutated protein

binds to the receptor, it begins to unfold and cross the lysosomal membrane.

Htt can evade these cellular processes, which causes it to remain in the cell (Lamark &

Johansen 2012). While CMA is not fully evaded by the mutant Htt, the protein can reduce the

selectivity of autophagy. The specific pathogenesis of this Htt reducing this selectivity is still

unknown; however it is well established that the ability to reduce chaperone-mediated autophagy can

contribute to the success of HD.

  30

Section 5: Cognitive and Psychological Effects of Huntington’s Disease and Prognosis (922)

Cognitive Effects

Many HD patients experience a variety of cognitive symptoms, which increase in severity as

the disease progresses (Table 5.1) (Roze et al. 2010; Turner 2002). Those who suffer from EOHD

can additionally have increased symptoms that include rigidity, oral motor dysfunction, and seizures.

These cognitive impairments can significantly interfere with patients’ autonomy, which can lead to

more severe psychological effects.

Table 5.1: The most common cognitive effects of HD organized by early and late disease duration. Table information obtained from: (Bachoud-Levi et al. 2001; Roze et al. 2010; Turner 2002).

Early Disease Late Disease Cognitive impairment Dementia Minor memory loss (immediate) Subcortical dementia Change in personality Increased memory loss Loss of attention span Loss of motor control Loss of comprehension

 

Psychological Effects

Neurobehavioural disorders are also common amongst HD patients, and can range in

both severity and time of onset (Roze et al. 2010; Durr 2007). Similarly to cognitive effects, the

psychological effects of HD also change and progress as the disease develops (Table 5.2). Anxiety is

most common, which can lead to depression, and reduced mental flexibility, where patients are more

fixed on their ideas and unwilling to reconcile another point of view. EOHD is also associated with

obsessive-compulsive disorders (OCD).

Table 5.2: The most common psychological effects of HD organized by early and late disease duration. Table information obtained from: (Roze et al. 2010; Durr 2007).

Early Disease Late Disease Anxiety Depression Loss of energy and appetite Reduced mental flexibility Dysphonia Increased irritability Low mood and self-esteem Increased aggression Hopelessness Violence

  31

Due to the association of HD with neurobehavioural disorders, patients with HD have a 5-

10% suicide rate, making them 5-10 times more at risk of suicide than the general population (Roze

et al. 2010). The suicide rate increases to 23% for patients with EOHD patients with psychotic states

similar to some forms of schizophrenia (Durr 2007). Meanwhile, 25% of HD patients attempt

suicide, with suicide ideation increasing at two time periods of their illness. Suicide ideation increases

from symptom onset to diagnosis and again during the midpoint of the disease when they must

begin to rely on others to assist them with daily activities.

Suicidal behaviours can range from attempting suicide to suicidal ideations (Main 1998).

Mood disorders and various neural behaviour disorders (as described above) can cause one to begin

to contemplate suicidal actions. Upon testing the brains of suicide victims, decreased levels of

serotonin, dopamine and norepinephrine were found in monoamine neurotransmitters at the

synapse of monoaminergic neurons (Caspi et al. 2003; Main 1998). The monoamine hypothesis of

depression suggests that depression, and if untreated, suicide, occur due to a lack of monoamine

neurotransmitters in the CNS (Delgado 2000). This is supported by successful treatments for

depression (antidepressants) designed to increase the amount of monoamine neurotransmitters in

the brain.

Antidepressant medications increase the amount of monoamines at the synapse by inhibiting

neuronal reuptake, which inhibits the intraneuronal metabolism (Elhwuegi 2004). Alternatively,

medication can increase the release of these monoamines by blocking the alpha-(2)-auto- and

heteroreceptors on monoaminergic neurons. This desensitizes the receptors allowing for more

central monoaminergic activity. Serotonin Selective Reuptake Inhibitors (SSRIs) fall into the latter

category of antidepressant medication. These medications function by blocking SERT. SERT is a

transporter that transports serotonin from outside the synaptic spaces to a presynaptic cleft

(Guzman 2013). Therefore, when SERT is blocked by SSRIs, there is an increase in serotonin

concentration in the synaptic spaces (Figure 5.1) (Guzman 2013, Norman 1999). More serotonin in

the synaptic spaces is associated with a reduction in the number of 5HT1A receptors that when

activated inhibit the firing of serotonergic neurons. Eventually, the decrease in the number of

5HT1A receptors (down-regulation) causes less inhibition of the firing of serotonergic neurons (i.e.

more firing of neurons). HD patients are prescribed antidepressants in attempts to mitigate their

suicide attempts and suicidal ideations (Ross & Tabrizi 2011).

  32

Figure 5.1: An image illustrating the blockage of SERT by the SSRI, which causes a higher concentration of serotonin in synaptic spaces (as illustrated by the purple crosses). This causes a reduction of 5HT1A receptors in the somatodendritic region (as illustrated by the U-shaped block). Figure source: (Guzman 2013).

Prognosis and Treatment

Life expectancy after onset of motor symptoms is 15-20 years for adult-onset HD and

shorter for juvenile HD (Roze et al. 2010). For the treatment of chorea, antipsychotics are most

widely accepted in advanced stages of this disease (Durr 2007). However, current therapies have

many adverse effects. Levodopa (L-dopa) is a dopaminergic drug that can improve voluntary

movements for patients (Figure 5.2). A side of effect of the drug is increased clumsiness and speech

related difficulties.

  33

Figure 5.2: The chemical structure of L-dopa. L-dopa is a chemical that is produced naturally in the human body and is a precursor for dopamine L-dopa can cross the blood-brain barrier and increases dopamine in the brain (Pan & Dendukri 2009). This drug is taken up by dopaminergic neurons and converted to dopamine (this conversion can happen in the peripheral nervous system and CNS) (Pubchem 2014). Figure source: (Pubchem 2014).

Currently, no cure for HD has been found; however there are treatment methods for HD

and other poly-Q repeat diseases being investigated (Walker 2007). These include gene silencing

with RNA interference and protease inhibitors, also known as gene therapy (Edelstein et al. 2007).

RNA interference involves small RNA molecules such as small interfering RNA (siRNA) and

microRNA (miRNA) (Anon, 2014.). Specifically, siRNA has been involved in HD research (Durr

2007, Shao, J. & Diamond, M.I., 2007). siRNA are derived from longer, double-stranded RNA and

can be produced in the cell or delivered experimentally (Anon, 2014.). These RNA molecules

selectively knockdown gene expression by degrading mRNA (Shao, J. & Diamond, M.I., 2007,

NCBI). A study has shown that manipulating RNA interference can improve motor control of mice

with the mutant Htt protein present in cells (Harper et al. 2005). However, the use of siRNA is more

challenging for diseases with more widespread CNS damage such as HD (Shao, J. & Diamond, M.I.,

2007). It is also more difficult to target the mutant gene only as the normal gene is vital for human

survival.

  34

Another potential method of HD treatment is protease inhibitors, specifically caspase

inhibitors. Caspases are cysteine proteases, which when activated initiate cell death by destroying key

parts of the cell and activating factors that mediate damage of the cell (Friedlander 2003). In

neurodegenerative diseases, weaker stimuli of cell death cause the activation of caspases to mediate

cell dysfunction before cell death. This causes significant cell dysfunction that could be the cause of

symptoms as caspases can be active for up to months at a time. Caspases have also been linked to

the appearance of toxic cleavage, and current research shows that they cleave polyglutamine

proteins to induce apoptosis and create toxic fragments (Shao & Diamond 2007). Caspase inhibitors

would reduce cell dysfunction and delay cell death to reduce symptoms.

  35

Supplementary Reading List

1. Warby, S.C., Graham, R.K. & Hayden, M.R., 2010. Huntington Disease. Available at:

http://www.ncbi.nlm.nih.gov/books/NBK1305/ [Accessed November 15, 2014].

The review article by Warby et al. titled “Huntington’s Disease” gives a detailed overview of

HD. It covers concepts such as disease characteristics, diagnostics, a clinical description of

the disease and management. This article provides the reader with basic information and

terminology used in other more specific articles, which is helpful for further comprehending

readings. The authors however do not go into great detail regarding the genetic aspects of

disease, but do discuss genetic counseling. Overall, the work presented in this paper provides

detailed background knowledge about the clinical aspects of HD.

2. Albin, R.L., Young, A.B. & Penney, J.B., 1989. The functional anatomy of basal ganglia

disorders. Trends in Neurosciences, 12(10), pp.366–375. Available at:

http://www.sciencedirect.com/science/article/pii/016622368990074X [Accessed October

24, 2014].

In the article titled “Genetics and molecular biology of Huntington’s disease” by Albin and

Tagle, a vivid description of genetics factors contributing to the development of HD is

outlined. One would be interested in reading this article as a teacher because it clearly

describes the characteristics of the interesting transcript gene, potential pathogenic

mechanisms, and the basic genetic characteristics of the disease. It is ideal to understand

these concepts before teaching since most of the understanding of how HD develops falls

into the field of genetics. This article would be very useful for background information

regarding chapter 4 of this unit.

3. Andrew, S.E. et al., 1993. The relationship between trinucleotide (CAG) repeat length and

clinical features of Huntington’s disease. Nature genetics, 4(4), pp.398–403. Available at:

http://dx.doi.org/10.1038/ng0893-398 [Accessed November 16, 2014].

  36

“The relationship between trinucleotide (CGA) repeat length and clinical features of

Huntington’s disease” by Andrew et. al discusses how the length of the poly-Q repeat is

directly related to the symptom’s of the disease. This article ties the genetic aspects of HD

with the physiological aspects allowing for a full understanding of the cause and effect

relationship present within the disease. This information is useful for teaching since having a

full understanding about how to declines can be used together ideal, since you can see

concepts through two different perspectives.

4. Glass M, Dragunow M, Faull RLM. The pattern of neurodegeneration in Huntington’s

disease: a comparative study of cannabinoid, dopamine, adenosine and GABAA receptor

alterations in the human basal ganglia in Huntington's disease. Neuroscience. 2000;97(3):505–

519. doi:10.1016/S0306-4522(00)00008-7. [Accessed November 10, 2014].

Glass et al. investigated various neurotransmitters involved in movement and motor control

and how the degeneration of these neurons or their receptors can lead to the symptoms of

HD. This paper would be very useful for the instructor to learn some background

information on the neurotransmitters involved in motor control and voluntary movement,

and to gain new perspectives on current HD research of this nature.

5. Chen JY, Wang EA, Cepeda C, Levine MS. Dopamine imbalance in Huntington’s disease: a

mechanism for the lack of behavioral flexibility. Front Neurosci. 2013;7:114.

doi:10.3389/fnins.2013.00114. [Accessed November 6, 2014].

This review article by Chen et al. specifically looks at dopamine imbalance in the striatum

and how this is a possible cause of HD. Due to its influence on the direct pathway,

dopamine is also a key neurotransmitter in Parkinson’s disease, and this article compares

these diseases. This literature would be useful to the instructor if they wished to know more

about dopamine and its connection to the direct pathway, and also if they wanted to look at

the differences between HD and PD. This would especially be relevant when teaching

chapter 3 of this unit.

  37

6. Roze, E. et al., 2010. Huntington’s Disease. In S. Ahmad, ed. Diseases of DNA Repair. Austin:

Landes Bioscience.

This book, specifically chapter 5, “Huntington’s Disease” provides descriptive and accessible

information about the cognitive impairment and neurobehavioural disorders associated with

the disease (chapter 4). This resource is beneficial as an overview of the topic of HD as it

provides context and includes some of the history of HD. It also contains information on

the topics covered in chapters 3.

7. Guzman,F. 2013, Mechanism of Action of SSRIs. Available at:

http://psychopharmacologyinstitute.com/antidepressants/ssris/mechanism-action-ssris/

[Accessed November 6, 2014].

This web page provides a step-by-step explanation of the SSRI mechanism with diagrams for

each step and an accompanying video. The thoroughness of this explanation and the

different methods is very useful in understanding this mechanism. This could potentially be

used as a teaching tool as well if students are having difficulties understanding the concept as

is it is very simple to play the video.

8. Purves, D., Augustine, G., Fitzpatrick, D., Hall, W., LaMantia, A., McNamara, J., & White,

L., 2008. Neuroscience 4th ed. Massachusetts: Sinauer Associates, Inc.

This textbook provides a wide range of information pertaining to neuroscience topics. It is

intended to be an introductory neuroscience textbook, however it also is an excellent

reference for basic knowledge on nervous system anatomy and nervous system circuits. This

book was used in explaining the mechanisms for voluntary movement and describing in

detail the pathways of the basal ganglia.

9. Halliday, G.M. et al., 1998. Regional specificity of brain atrophy in Huntington’s disease.

Experimental neurology, 154(2), pp.663–72.

  38

This paper discusses how Huntington's disease detriments brain volume in humans. This

paper addresses that in addition to the external symptoms of Huntington's disease patients,

internal effects are also a concern. This paper is an effective paper that integrates most of the

concepts learned throughout the unit.

10. Smith, Y. et al., 1998. Commentary Microcircuitry of the Direct and Indirect Pathways of the

Basal Ganglia. Neuroscience, 86(2), pp.353–387.

A commentary with much detail on the pathways and the methods of determining these

pathways. This paper is important because it provides an insight on how research in

neuroscience is performed to determine intricate pathways such as the basal ganglian

pathways.

11. Andre, M. et al., 2011. Differential Electrophysiological Changes in Striatal Output Neurons

in Huntington ’ s Disease. The Journal of Neuroscience, 31(4), pp.1170–1182.

This paper describes the difference in the neuronal outputs in the basal ganglia between

normal patients and patients with Huntington's disease. This paper allows for the application

of the concepts learned in sections 1 and 2.

  39

Glossary

A Aggregates - Fragments of misfolded proteins that have both soluble and insoluble terminals

(Landles & Bates 2004).

Antipsychotics/neuroleptics - Class of psychiatric medications used to reduce or relieve

symptoms of psychosis such as delusions, hallucinations (Centre for Mental Health and Addiction

2012).

Autosomal dominant – A classification in genetics where a single mutant allele, inherited from

either parent is sufficient to produce the trait, resulting in phenotypic expression (Gallagher 2005).

Autophagy - A cellular pathway used to eliminate toxins from cell by recycling organelles, proteins,

and assists in apoptosis (Landles & Bates 2004).

B

Basal ganglia - A group of nuclei located deep in the subcortical white matter of the frontal lobes

that organize motor behavior. The caudate and putamen and the globus pallidus are the major

components of the basal ganglia; the subthalamic nucleus and substantia nigra are often included

(Purves et al. 2008).

Brainstem center - The vestibular nucleus, superior colliculus, and reticular formation which

contain upper motor neurons and control basic movements and postural control (Purves et al. 2008).

C

Cerebellum - Prominent hindbrain structure concerned with motor coordination, posture, and

balance. Composed of a three-layered cortex and deep nuclei; attached to the brainstem by the

cerebellar peduncles (Purves et al. 2008).

Chaperone Proteins - Proteins that aid in the folding and unfolding of other proteins (Lodish et al.

2013).

Chorea - Jerky, involuntary movements associated with damage to the basal ganglia. A characteristic

symptom of Huntington's disease (Ross & Tabrizi 2011).

D

Descending systems - The motor cortex and the brainstem centers, which are composed of upper

motor neurons (Purves et al. 2008).

  40

Direct pathway - The pathway of the basal ganglia that increases thalamic activity

G

Gene silencing - The suppression or interruption of gene expression at transcription of translation

(NCBI 2014).

GABAergic Medium-Sized Spiny Projection Neurons (MSNs) - A type of inhibitory neuron

that constitutes 90-95% of the striatum. These neurons play a key role in generating movement

(Chen et al. 2013).

Globus pallidus externus - Part of one of the major nuclei that make up the basal ganglia; relays

information from the neostriatum to the subthalamic nucleus (Purves et al. 2008).

Globus pallidus internus - Part of one of the major nuclei that make up the basal ganglia in the

cerebral hemispheres; relays information from the neostriatum to the thalamus (Purves et al. 2008)

H

HAP-1 protein - A protein that aids in DNA homology repair (Robson et al. 1992).

Histones - Cellular organelles that package DNA into nucleosomes (Freeman 2008).

Hyperkinesia - Increase in voluntary muscular movement (Gepshtein et al. 2014).

Hyperpolarization - The change in a cell’s membrane potential that makes it more negative.

Hypokinesia - Decrease in voluntary muscular movement (Gepshtein et al. 2014).

K

Kinase Activity - The action of the kinase enzyme aiding in phosphorylation of various proteins.

L

Ligand-Gated - Opening of the ion channel is regulated by the presence or absence of a required

molecules.

Local circuitry - Neurons that receive synaptic input from higher order systems or sensory systems

and output to the lower motor neurons (Purves et al. 2008).

Lower motor neurons - Neurons that receive synaptic input from the local circuitry and output to

muscles to directly control movement (Purves et al. 2008).

  41

M

Motor cortex - The region of the cerebral cortex lying anterior to the central sulcus concerned with

motor behavior; includes the primary motor cortex in the precentral gyrus and associated cortical

areas in the frontal lobe (Purves et al. 2008).

N

Nascent peptide - A peptide while being formed by a ribosome before it is folded into its 3-

dimensional shape (Lodish et al. 2013).

Neostriatum - Structure involving the caudate and the putamen that receives excitatory input from

the cortex and sends inhibitory output to the globus pallidus (Nicholls et al. 2012).

Neurobehavioural disorders - Cognitive, behavioral and emotional impairments associated with

brain disease, transient and permanent brain impairments and/or injury (Zasler et al. 2013).

N-terminals - The end of a protein that is a free amine group (Speicher et al. 2009).

Nuclei - Structures in the central nervous system composed of neurons that differ from other

nuclei by their synaptic interactions and functions in the brain (Nicholls 2012).

P

Pathogenic allele - When certain repeats expand in later generations (in terms of HD) (Roze et al.

2010).

Polyglutamine diseases - A family of neurodegenerative diseases that have a CAG triplet repeat

expansion (Shao & Diamond 2007).

Primary motor cortex: A major source of descending projections to motor neurons in the spinal

cord and cranial nerve nuclei. It is located in the precentral gyrus and essential for the voluntary

control of movement (Purves et al. 2008).

Proteostasis – Cellular homeostasis of proteins (Hartl et al. 2011).

S

Sensory inputs - Synaptic inputs from the sensory organs (i.e. the eyes, nose, ears, tongue, skin)

SERT - A transporter that moves serotonin from outside the synaptic spaces to a pre-synaptic cleft

(Guzman 2013).

Subcortical dementia - Degenerative disorder caused by lesions in the basal ganglia, brain-stem

nuclei and cerebellum (Turner 2002).

  42

Substantia nigra - Nucleus at the base of the midbrain that receives input from a number of

cortical and subcortical structures. The dopaminergic cells of the substantia nigra send their output

to the neostriatum while the GABAergic cells send their output to the thalamus (Purves et al. 2008)

Subthalamic nucleus - A nucleus in the ventral diencephalon that receives input from the GPe and

participates in the indirect pathway for motor control (Purves et al. 2008).

Suicidal ideation - Occurrence of suicidal thoughts (Gliatto 1999).

T

Threshold Potential - The voltage across the cell membrane of a cell required to fire an action

potential.

U

Upper motor neurons - Neurons that gives rise to a descending projection that controls the activity

of lower motor neurons in the brainstem and spinal cord. (Purves et al. 2008).

  43

Student Manual: Introduction

Huntington's Disease (HD) is a neurodegenerative disease that impairs motor control and is

caused by genetic dispositions that attack the mechanisms of voluntary movement. Movement is a

highly regulated process that can be broken down to simple circuitry among structures in the

nervous system. These structures include the sensory inputs, the brainstem, the brainstem centers,

the motor cortex, the basal ganglia, the cerebellum, the local circuit neurons, and the lower motor

neurons.

Movement is highly regulated by the direct and indirect pathways of the basal ganglia

(Figure S.1). Implications in these pathways are ultimately what lead to HD symptoms. Patients

suffering from HD also experience significant volume loss in the cortex and in the striatum. HD is

predominantly associated with defects in the indirect pathway of movement because of the inability

to control the inhibition of movement.

Figure S1: The direct and indirect pathways. The direct pathway initiates movement and the indirect pathway inhibits movement.

  44

The three main neurotransmitters involved in the synapses within the basal ganglian

pathways are: gamma-aminobutyric acid (GABA), dopamine, and glutamate. GABA is inhibitory

while dopamine and glutamate are excitatory neurotransmitters (Figure S.2).

Figure S2: A schematic diagram of the circuitry around the basal ganglia including the neurotransmitters associated with the synapses.

GABA functions as the inhibitory neurotransmitter within the main connections in the basal

ganglia circuit (i.e. neostriatum to the globus pallidus and globus pallidus to the thalamus). Defects

on GABA receptors or on the neurotransmitter itself results in significant implications in both the

indirect and direct pathways of voluntary movement.

Dopamine functions as an excitatory neurotransmitter between the subthalamic nucleus pars

compacta (SNc) and the neostriatum. This stimulates the activity of the neostriatum to further allow

it to follow the direct pathway. Imbalances in dopamine levels or destruction of dopaminergic

neurons and their receptors decreases one’s ability to perform voluntary actions, and is thought to

be the cause of the long-term decrease of voluntary movements (hypokinesia) seen in patients with

HD.

Glutamate is an excitatory neurotransmitter used in the connections between the cortex and

the neostriatum and between the subthalamic nucleus and the GPi. Impairment in the uptake of

glutamate has been found to contribute to HD as it slows down the excitatory activity against the

GPi and thus causes less inhibition on the thalamus, creating excessive movements characteristic of

HD.

  45

HD is a genetic disease that is characterised by a trinucleotide repeat. Individuals with a large

repeat of CAG (the codon for glutamine) at the 5’ end of the transcript gene 15 code located on

chromosome 4 develop HD. The mutant allele that aids in the coding of excessive CAGs can be

inherited either maternally or paternally. These repeats can expand depending on various mutations

that can occur during the transcription process. This means that offspring may develop HD despite

their parents not developing the disease. Once the mutated transcription occurs, a mutated

Huntingtin protein (Htt) is produced.

The Htt protein can negatively interact with cells (especially neurons in the central nervous

system) since mutant proteins are generally misfolded. The Htt protein evades regular cellular

processes involved in protein folding. Aggregates (small fragments of the misfolded protein) can

interact with neurons and synapses resulting in a decrease in neurological function. The aggregates

can bind to various components in the basal ganglia, causing a loss of motor control.

There are a variety of clinical symptoms associated with HD including cognitive impairment,

neurobehavioural disorders, and chorea. Cognitive impairment is usually the first of the clinical

symptoms. For HD patients, cognitive impairment can lead to dementia, which is characterised by

memory loss, changes in personality, and learning impairment. Chorea, a well-known symptom of

HD actually has a later onset. Early onset HD (EOHD) patients have more severe symptoms that

include rigidity, oral motor dysfunction, and seizures. Most patients also manage neurobehavioural

disorders, most commonly anxiety. They also have a higher suicide rate of 5-10%, with an even

higher suicide rate in EOHD patients. Additionally, 25% of HD patients have attempted suicide,

with suicide ideation peaking after diagnosis and at the midpoint of disease progression.

Recent research indicates that neurobehavioural disorders are associated with decreased

levels of monoamine neurotransmitters (serotonin, dopamine, norepinephrine). As such,

antidepressants function by increasing their release or by blocking the reuptake of monoamine

neurotransmitters. Serotonin Selective Reuptake Inhibitors (SSRIs) follow this mechanism by

blocking the SERT transporter, which moves serotonin from outside synaptic spaces into the

presynaptic spaces. This increases serotonin concentration in the synaptic spaces and ultimately

increases serotonin transmission.

In conclusion, through the example of Huntington’s disease, this unit will walk you through

the pathways of voluntary movement in the brain and genetic concepts that are necessary to

understand what may go wrong in the nervous system.

  46

Figure S3: An image illustrating the blockage of SERT by the SSRI, causing a higher concentration of serotonin in synaptic spaces (as illustrated by the purple crosses). This is associated with the reduction of 5HT1A receptors in the somatodendritic region (as illustrated by the U-shaped block (Guzman 2013).

  47

Instructions For Students (468)

Scenario

You are members of the iSci Medical Research Team and have been tasked to distinguish the medical aspects of Huntington’s disease (HD). Throughout a series of lectures and activities you will be able to understand how HD occurs and how physicians treat the disease in attempts to increase the quality of life of those who suffer with HD. Additionally, you will gain a thorough understanding of the various pathways of HD and how they can affect the body.

Learning Objectives

Biology

A basic understanding of brain anatomy and signaling pathways regarding voluntary movement will be expected upon completion of this unit. This includes the comprehension of direct and indirect signaling pathways in the basal ganglia. Additionally, the concepts of neurotransmitters and their function in voluntary movement pathways must be explored. Specifically you will investigate the functions of GABA, dopamine and glutamate and their corresponding receptors.

Biochemistry

In depth concepts and applications of: transcription, translation, protein formation and protein folding will be covered. Exceptions to these rules made by mutations will also be discussed through the example of HD. Genetic predisposition will also be covered.

Chemical Biology

Neurotransmitters can also be considered a part of chemical biology. How they interact with receptors must be considered while investigating elements of HD such as chorea. Drugs such as L-dopa and SSRIs are used to treat the symptoms of HD. You must have a full understanding of the basic interactions of these drugs in the brain.

Psychology

It is expected that you will become familiar the various cognitive effects of HD once completing this unit. The symptoms of depression will be discussed. Other symptoms of HD that can cause a decrease in overall life quality should be understood.

**All of these disciplines are taught in the context of neuroscience**

  48

Assessments & Marking

Assessments Amount Total % Worth

Activities 4 30 Participation 1 10

Class discussion of topics 1 15 Research take home question 1 15

Unit test 1 30

Note: Each activity will be worth the same amount however activity 1 will go solely towards your participation mark; your participation mark will also be affected by how much you contribute to class

Unit Timelines and Deadlines

Lecture Topic In-Class Activity Due

1 Brain Anatomy and Voluntary Movement Circuits in the Brain N/A

2 The Basal Ganglia and the Direct and

Indirect Pathways for Voluntary Movement

N/A Next

class

3 Neurotransmitters in Movement Investigations of Voluntary

Movement

Next

class

4 Genetics Predisposition of HD HD Diagnosis and Prognosis –

Part 1: Genetics

Next

class

5 Cognitive and Physiological Effects of HD

& Prognosis

HD Diagnosis and Prognosis –

Part 2: Clinical Symptoms

Day of

Unit Test

Preparations Please watch the videos outlined in the “Supplementary Reading List” to review transcription and translation. Other videos will introduce you to the topics covered in the unit.

  49

Supplementary Reading List

1. Green, H., 2014. 4 Psychological Terms That You’re Using Incorrectly, United States of

America: Youtube. Available at: https://www.youtube.com/watch?v=8pK5FuptsSQ

[Accessed November 20, 2014].

This source presents supplementary information on the different neurobehavioural disorders

mentioned in section 5 and their corresponding symptoms. This video also provides a social

context for the uses of words such as “OCD”, “schizophrenia” and “anxiety”, making it very

accessible for grade 12 students. Additionally, it emphasizes the stigma surrounding mental

illness, which is essential to understanding neurobehavioural disorders.

2. The Brain—Lesson 2 How Neurotransmission Works - YouTube. Youtube. Available at:

http://www.youtube.com/watch?v=p5zFgT4aofA. [Accessed November 21, 2014].

This video provides a brief review of how neurotransmission occurs in the brain, and it

would be a good video to help the student recall this key process before starting the unit.

3. Nicholls, J., Martin, A., Fuchs, P., Brown., D., Diamond, M., & Weisblat, D., 2012. From

Neuron to Brain 5th ed. Massachusetts: Sinauer Associates, Inc.

This source is a textbook that provides a concise section on the circuitry behind motor

control (Chapter 24) as is described in Section 1. This textbook also provides a well-written

comprehensive section on the basal ganglia circuitry and the direct and indirect pathways in

regulating voluntary control. This source is to be taken as a supplemental reading to help

with understanding the pathways described in this unit.

4. Hasudugan, Armando, 2014. Transcription and Translation Overview. Youtube. Available at:

https://www.youtube.com/watch?v=6YqPLgNjR4Q. [Accessed November 20 2014].

This video gives an accurate overview of the cellular procedures of both transcription and

translation. The information presented was crosschecked with the Textbook “Biological

  50

Sciences” by Freeman (2008) to ensure validity. The video defines what chromosomes, genes,

histones and DNA are. These are helpful to know prior to beginning this unit. The point of

this video is to refresh students on these key biochemistry topics prior to learning about the

HD mutation in this process since it will not be reviewed within the unit.

5. CramYourMedicine, 2014. The Basal Ganglia - Direct and Indirect Pathway., United States

of America. Available at: https://www.youtube.com/watch?v=82oIHBGDoiI. [Accessed

November 20, 2014].

This is a useful video that walks through the direct and indirect pathways of the basal ganglia.

It may be shown to the students after teaching the concepts to make their understanding

more concrete. It is a good resource because the author clearly identifies common areas of

confusion.

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Contributions

Angelico

• Did background research for chapters 1 and 2 • Wrote drafts of chapters 1 and 2 • Created the activity that incorporates concepts from both chapters 2 and 3 • Wrote and edited the teacher’s introduction • Made major revisions to the student manual introduction • Initially provided 4 paragraphs for the student introduction • Wrote 2 annotations for the student manual and 4 for the teachers manual • Organized a draft and feedback for the group

Jaime

• Did background research for chapter 3 • Wrote drafts for chapter 3 • Created activity for chapter 1 • Formatted the final document text • Wrote 1 annotation for the student manual and 2 annotations for the teachers manual • Wrote 2 paragraphs of the student introduction

Dakota

• Did background research for chapter 4 • Wrote a draft of chapter 4 • Wrote the student instructions • Wrote teachers instructions • Made activity for chapter 4 • Edited all in text and reference lists • Initially provided 2 paragraphs for the student introduction • Wrote and edited teachers instructions • Wrote 3 annotated entries for teachers manual and 1 for student manual

Eva

• Did background for research for chapter 5 • Wrote a draft of chapter 5 • Wrote activity for chapter 5 • Ran final documentation through “grammarly” to edit • Wrote 1 annotated entry for the student manual and 2 for the teachers manual • Wrote 2 paragraphs for the student introduction

Note:

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• All group members edited the document • All group members did their own in text and final reference entries • All group members contributed to the glossary