Huntington’s

Disease Iain Conlon / D00128197

Decleration

I hereby declare that the project work entitled “Huntington’s Disease” submitted to the Dundalk Institute of

Technology, is a record of an original work done by me, Iain Conlon, under the guidance of Sinead

Loughran, Faculty Member, Faculty of Science, Dundalk Institute of Technology, and this project work has

not performed the basis for the award of any Degree or diploma and similar project if any.

Acknowledgements

I would like to thank my original mentor, Dr. Sinead Loughran, for all the help and support she has given

me throughout the process of writing this literature review. I would also like to thank Ronan Bree for his

informative lectures with regard to researching for, writing and presenting literature reviews throughout the

semester. Finally, I want to thank Dr. Gillian Lambe for taking me as her protégé and in advance for

reviewing and correcting my work.

Contents Introduction ............................................................................................................................................. 3

What is Huntington’s Disease? ........................................................................................................... 3

Symptoms of Huntington’s disease ..................................................................................................... 3

Chorea ............................................................................................................................................. 3

Depression ....................................................................................................................................... 3

Neuropsychiatric symptoms ............................................................................................................ 4

Impaired cognitive ability ............................................................................................................... 4

Diagnosis and Diagnostic procedures ................................................................................................. 4

The brain, medium spiny neurons and GABA ........................................................................................ 4

Pathophysiology ...................................................................................................................................... 4

Overview ............................................................................................................................................. 4

Htt and mHtt ....................................................................................................................................... 5

Age and Huntington’s disease ............................................................................................................. 5

Potential pathophysiological pathways ............................................................................................... 6

Overview ......................................................................................................................................... 6

mHtt protein aggregation ................................................................................................................ 6

Transcription ................................................................................................................................... 7

Apoptosis and Mitochondrial involvement ..................................................................................... 7

Other possible causes ...................................................................................................................... 8

Treatment ................................................................................................................................................ 8

Overview ............................................................................................................................................. 8

Neuroleptics ........................................................................................................................................ 8

Dopamine depleters ............................................................................................................................ 8

Antidepressants ................................................................................................................................... 9

Therapeutic treatment ......................................................................................................................... 9

Latest advances ................................................................................................................................... 9

Conclusion .............................................................................................................................................. 9

Bibliography ......................................................................................... Error! Bookmark not defined.

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disease. The disease causes chorea,

decrease in cognitive ability, neuropsychiatric symptoms and other symptoms. It can be detected using genetic

tests. It is caused by an abnormality on the Huntingtin gene which causes a polyglutamine (polyQ) of over 35 to

be created on the Huntingtin protein, in affect, creating mutant Huntingtin protein, or mHtt. The length of the

polyQ repeat length seems to affect the age of onset of HD. This mutant huntingtin protein is thought to cause

specific neurodegeneration of striatal medium spiny neurons (MSN). It is not known exactly how the mHtt may

affect the MSNs but there are many theories of possible pathophysiological pathways. mHtt aggregation is

thought to have a major affect on its toxicity to MSNs, whilst the mHtt interactions with apoptotic and

translation proteins may also be the root of the toxicity. mHtt may have an affect on the mitochondria to cause

an apoptotic pathway. As there’s no known cause to the disease, the main treatments to the disease are

symptomatic ie. treating chorea, depression and cognitive impairments. However, studies on prions disease

show that neurodegeneration can be completely stopped with the use of a drug called PERK. This may

translate to provide a basis on how to prevent the HD neurodegeration. In this piece, all aspects of HD are

reviewed with concentration on the possible pathophysiological pathways.

Introduction

What is Huntington’s Disease?

Huntington’s disease (HD) is a hereditary

neurodegenerative disease (Kent, 2004). HD is

autosomal dominant ie. if a father in a family has it but

the mother does not, any child of the two will have a

50% chance of getting the disease. The disease was

first described by George Huntington, in 1872, as

Huntington’s Chorea, due to the observation one of the

main symptoms, chorea, in his patients (Adam &

Jankovic, 2008). Some other symptoms associated

with HD, aside from chorea, are impaired cognitive

ability, depression, dementia and other motor function

impairments (Stanley, 2009).

HD is caused by a defect in the Huntington

gene, located on the short arm of chromosome 4

(Adam & Jankovic, 2008). This defect is an unusually

large amount of polyglutamine, CAG triplet, repeats

(Ross & Tabrizi, 2011). This unusual amount of

polyglutamine repeats always results in the creation of

the mutant Huntingtin protein, mHtt, that somehow has

a toxic effect on the brain, and specifically, medium

spiny neurons (Damiano et al., 2010). It is not known

exactly how, or if, the mutant Huntingtin protein is

neurotoxic but there is much research on the subject of

Huntington’s pathophysiology happening at the

moment, and some ideas will be discussed in this

paper.

HD is not very prevalent when it is compared

to other diseases as it only happens in every 4 – 8

persons in every 100’000. Other neurodegenerative

diseases are a lot more common. Its onset usually

occurs in adults around 35 – 45 years of age (Ross &

Tabrizi, 2011), however the age of onset of symptoms

correlates with the amount polyglutamine repeats

present (Chen, Ferrone & Wetzel, 2002). Death usually

occurs about 15 – 20 years after onset of symptoms

(Ross & Tabrizi, 2011). Death usually happens by the

HD sufferer falling. There is no known cure for HD

but there are many drugs and treatments that can help

the different symptoms of the disease (Adam &

Jankovic, 2008).

Symptoms of Huntington’s disease

There are many different symptoms that are associated

with HD. There are three different types of symptoms

involved with HD; Physical (mainly motor), emotional

and cognitive symptoms (Stanley, 2009). Below are

the main 3 studies symptoms of HD.

Chorea

Chorea is a symptom in which the body makes

uncontrollable “jerky” movements (Stroke, 2010). It

seems to be the most common symptom associated

with HD The disease was originally called

Huntington’s Chorea due to these involuntary

movements looking like a dance (Cha, 2000). Natually,

chorea progressively gets worse as the disease

progress’. These movements are mainly seen in the

trunk, legs, arms and face of HD sufferers. HD causes

death of medium spiny neurons and as they are

GABAergic (GABA secreting) neurons, this results in

a decrease in GABA activity in the body, causes these

movements (Boecker, 2013).

Depression

Depression also seems to be a common emotional

symptom caused by HD. Depression is known to lead

suicidality. There may be a higher rate of suicide in

HD person than in a non HD person (Hubers et al.,

2012). Although, a depressed mood might be due to

HD itself, actual depression might not actually be a

symptom of HD (Fiedorowicz et al., 2011). A history

of depression, or attempted suicide, may make a

person with HD more likely to be suicidal during HD

(Fiedorowicz et al., 2011). Interestingly, a study done

mentioned that 25% of the people in the study with HD

had attempted suicide (Walker, 2007).

This worsened suicidal behaviour may be due to

having to deal with other symptoms associated with

HD.

Neuropsychiatric symptoms

Neuropsychiatric symptoms in HD are very prevalent

(Paulson et al.,2001). The most common of them are

dysphoria, agitation and irritability, whilst apathy and

anxiety are also present in more than 50% of HD

sufferers (see table 1) (Paulson et al., 2001).

Table 1: Study done by Paulsen et al.(2001) regarding

neuropsychiatric symptoms on HD sufferers.

NPI Scale Frequency* Mean SD

Dysphoria 69.2 3.12 3.46

Agitation 67.3 2.88 3.32

Irritability 65.4 2.63 3.11

Apathy 55.8 2.79 4.02

Anxiety 51.9 1.96 3.14

Disinhibition 34.6 1.29 2.77

Euphoria 30.8 1.04 2.27

Delusions 11.5 0.75 2.63

Abberant motor 9.6 0.60 2.18

Hallucinations 1.9 0.23 1.66

N = 52; NPI = Neuropsychiatric inventory; *percent of

patients with an NPI score ≥1;

Most of the symptoms shown above can be treated

specifically.

Impaired cognitive ability

The problems with cognitive ability start to begin

before the onset of motor problems, like chorea

(Milnerwood & Raymond, 2010). These cognitive

symptoms presents a difficulty to the HD sufferer from

understanding people, learning, using memory to

attention keeping. Cognitive ability is usually in steady

decline as the disease progresses and can eventually

lead to a HD sufferer forgetting their family and

friends.

Diagnosis and Diagnostic procedures

There a number of ways to test if a person is positive

for having HD. Brain imaging, such as fMRI and PET

scans, can show volume and appearance differences in

the brains striatum caused by the disease (Reviewed in

Walker, 2007). Family history of the disease is also a

good indicator as to whether a person may have it. The

most effective test that can be done is the genetic test,

which tests for the mutant Huntingtin allele (Reviewed

in Walker, 2007). This test, however, can be cost

effective like many other genetic tests. Other tests that

can be done are tests for chorea and cognitive ability or

impairment.

The brain, medium spiny neurons and

GABA In the brain, there are specific neurons called medium

spiny neurons (MSNs), and these are mainly located in

the striatum of the brain (Steiner & Tseng, 2010). The

MSNs are named due to their appearance; which is

spiny-like, with projections that are medium in size

compared to other neurons (see figure 1) (Steiner &

Tseng, 2010). MSNs are GABA secreting neurons, or

are GABAergic. GABA, or gamma-Aminobutyric

acid, is the most important inhibitory neurotransmitter

in the human body and is synthesized in the MSNs by

glutamic acid decarboxylase (GAD) enzyme

(Reviewed in Steiner & Tseng, 2010). As GABA is an

inhibitory neurotransmitter, it helps prevent an

excitatory response in the body ie. it helps to control

movements and the conductive flow of energy around

the brain and body.

Figure 1: Striatal medium spiny neuron (Ellender, 2013)

Pathophysiology

Overview

A polyglutamine sequence (polyQ) is a triplet of

nucleotides that contain cytosine, adenine and guanine,

in that order (Gil & Rego, 2008). Interestingly, every

human has a number of polyglutamine repeats in their

bodies but Huntington’s disease sufferers have too

many of them. There are many different polyglutamine

repeat disorders known, such as DRPLA

(dentatorubropallidoluysian atrophy), SBMA

(spinobular muscular atrophy) SCA1 (spinocerebellar

ataxia type 1) and some others (Education, 2010). A

person may have up to about 34 polyQ repeats and will

not develop HD, but if somebody has over 40 of these

repeats they will definitely be affected by HD (Sugars

& Rubinsztein, 2003). In between 35 and 39 polyQ

repeats may or may not present as HD in a person, it

can come down to luck (Sugars & Rubinsztein, 2003).

In Huntington’s disease the short arm of chromosome

4 contains the 40+ polyQ repeats (see figure 2)

(Reviewed in Kent, 2004).

Figure 2: Huntingtin gene on the 4th chromosome (Collins,

1999)

Htt and mHtt

In HD, the mutant Huntingtin protein (mHtt) is then

coded from the abnormal length of PolyQ repeats.

Normally, Huntingtin protein (htt) is just coded from

the Huntingtin gene in a normal person (Landles &

Bates, 2004). Normal Huntingtin protein can be found

in dendrites, the nucleus, mitochondria, cell body and

nerve terminals, however, the actual function of htt is

unknown (Landles & Bates, 2004). Some research

suggests that htt plays an important role with neuronal

cells and may be essential in brain development before

birth (Anon, 2013). Htt may also have roles in clathrin

mediated endocytosis, post-synaptic signalling and

neuronal transport (Landles & Bates, 2004). The

Huntingtin protein (htt) is a protein which contains 5

HEAT sequences, and a N-terminus containing the

polyglutamine and polyproline regions (see figure 3)

(Uniprot, 2010). It is mainly found in an alpha-helical

shape and in extended conformations (Uniprot, 2010).

Htt is thought to be able to easily interact with

different partners, and mainly through the N-terminus

(Reviewed in Ross & Tabrizi, 2011). There is still

much research going on as how to normal Huntingtin

protein affects the brain. Studying the normal

Huntingtin protein may give an insight into how to

prevent the mutant Huntingtin protein from causing

HD.

Neurodegeneration is what causes the affects

of the disease but impaired dopamine has been seen in

pre-symptomatic HD without the death of neurons

(Bibb et al., 2000). The main protein involved with

HD, mHtt, has a deadly degenerative effect on medium

spiny neurons (MSN) in the brain (Hickey &

Chesselet, 2003). It is not known why mHtt seems to

specifically act on MSN and no other neurons in the

body, but it could be due to an interaction between

mhtt and Rhes protein, which is mainly found in

striatal MSNs (Ross & Tabrizi, 2011). By the

advanced stage the disease, up to 95% of all MSNs in

the brain could be lost (Reviewed in Hickey &

Chesselet, 2003) The striatum in the brain is where

MSNs seem to be most affected initially, but

degeneration of MSNs then spreads to further areas of

the brain (Reviewed in Sugars & Rubinsztein, 2003).

As the death of MSNs occurs, there is a subsequent

loss or decrease of GABA in the brain, which might

attribute to some HD symptoms such as Chorea or

some neurospsychiatric symptoms. There is also some

evidence that hyperechogenic lesions form in the

caudate nucleus and substantia nigra of a HD brain

(Postert et al., 1999). The study shows that as the

disease progresses in its severity, the hyperechogenic

lesions may become larger and more common (Postert

et al., 1999)These lesions, however, might be related

and correlate with the degree of MSN cell death

(Postert et al., 1999).

Figure 3: Structure of htt protein (Ross & Tabrizi, 2011)

The PolyQ, or polyglutamine, sequence can be seen on the N

terminus of the protein. The protein contains 5 HEAT repeats and

it’s unknown how long the protein actually is.

Age and Huntington’s disease

The age of onset of HD is thought to be directly linked

to the amount of polyQ repeats that are present in the

person (see figure 4). The longer the length of CAG

repeats on mHtt, the earlier the disease onset is thought

to occur (Uniprot, 2010). From 80 – 100 CAG repeats

would cause Juvenile HD (Reviewed by Hickey &

Chesselet, 2003), which affects children under the age

of 15. As the mutant gene is passed down from a

parent to child, the amount of polyQ repeats that can

be coded increases. Therefore, this increases the risk of

earlier disease onset to the child.

Figure 4: CAG repeat length against age of onset of HD

(Walker, 2007)

From figure 4, it is easy to see how the CAG length is

inversely proportional with the age of onset of HD.

Some of the shortest CAG repeats show an age of

onset from about 35 – 75, whilst the longest CAG

length, shows onset occurred at the age of 20 (Walker,

2007). In the case of HD, genetic testing could

possibly be used to predict the age of onset using CAG

length. Although, many possible mutant Huntingtin

gene carriers may not want to know their fate with

regards to this disease.

Age

of

onse

t

Potential pathophysiological pathways

Overview

There are many theories of ways in which the mutant

Huntingtin protein may have a neurodegenerative

affect on medium spiny neurons of the striatum. Since

the htt gene was found back in 1993 (Huntington’s

Disease Collaborative Research Group, 1993), much

research was done into the possible pathophysiology of

the Huntingtin protein after it is coded. It is possible

that the protein may affect apoptosis, functions of the

mitochondria, transcription and other cellular

processes, but one of the most common ideas in the

theories is that the mHtt clump together to form

aggregates (Chen, Ferrone & Wetzel, 2002; Truant et

al., 2008; Bates, 2003; Bocharova et al., 2009).

There are a few different model systems that

can be used by scientists when they are trying to

determine how mHtt may affect cells (Ross & Tabrizi,

2011). Cell models, which can derived from patients

with Huntington’s disease, are good in-vitro models

due to their ability to act similar to neurons in the body

(Ross & Tabrizi, 2011). Mouse models are one of the

most commonly used models. They offer a decent way

of obtaining changes in behaviour in the test subject,

which obviously can not be done on any in-vitro

models. The phenotypes of the disease can be seen

very quickly after infection (Ross & Tabrizi, 2011).

Yeast models, invertebrate models and other

mammalian models are also used (Bocharova, Chave-

Cox, Sokolov, et al., 2009; Ross & Tabrizi, 2011).

mHtt protein aggregation

In most studies, aggregation of mHtt seems to be a

common theme. Bates (2003) believes that it may be

the centre of the pathophysiological pathway of the

disease and that aggregation is the basis of MSN

degeneration in the disease in some way. Aggregation

of the proteins only seems to occur with Huntingtin

proteins containing at least 36 polyQ repeats (ie.

mutant Huntingtin protein) and any proteins with less

than 36 polyQ repeats do not seem to aggregate, so

they do not form any possibly toxic structures

(Reviewed in Truant et al., 2008). Proof of this was

found when insertion of long polyQ repeats was added

to a gene, aggregates were subsequently formed

(Reviewed in Hickey & Chesselet, 2003). Aggregation

seems to happen because of a hydrophobic interaction

on the N-terminus of the mHtt proteins (Ross &

Tabrizi, 2011). It is hypothesised that these

interactions could be targeted as a way of preventing

aggregation, and therefore possibly preventing the

disease (Ross & Tabrizi, 2011). Aggregation

inhibitors, such as sulfobenzoic acid derivatives, could

aid in prevention of aggregation. However, the actual

creation method of the aggregates is not fully

understood. Chen, Ferrone & Wetzel (2002) had one

theory to how they were created (see figure 5).

Figure 5. A model for polyQ aggregate nucleation and

extension.

In this model, nucleation consists of an unfavourable transition

(step a) from an extended , statistical coil state corresponding to the

aggregation nucleus. The elongation process consists of an initial

binding (step b) of the nucleus to an extended conformation

monomer, followed by consolidation of structure (step c) that

generates a new binding site for monomer. The resulting species

binds to another extended chain monomer (step d) to continue this

process (Chen, Ferrone & Wetzel, 2002)

Bizarrely, the location of the aggregates, when studied

after death of HD patients, does not seem to correlate

with the location of neuron cell death (Reviewed by

Hickey & Chesselet, 2003). PolyQ length and

nucleation of mHtt, however, does somehow have a

relationship with the degeneration of MSNs as the

quantity of aggregates was found to correlate with

toxicity of the MSN (Sugaya & Matsubara, 2012).

Along with this, a study of a yeast-model of HD shows

that the PolyQ stretches create aggregates in the

cytoplasm and the nucleus, along with disturbing the

cell cycle (Reviewed by Bocharova et al., 2009).

These results prove that while the aggregates

themselves might not be the cause the MSN cell death,

their formation may somehow lead to the death of

MSNs.

Hickey & Chesselet (2003) make a link

between the mutant Huntingtin protein aggregates and

transcription. There is also evidence explaining that

large numbers of APCs (Anaphase promoting

complexes) due to the proteasome activity with mHtt

aggregates may have a harmful effect to the cell (see

figure 6) (Bocharova, Chave-Cox, Sokolov, et al.,

2009). Large numbers of APCs have been related to

problems in Alzheimer’s disease (Reviewed in

Bocharova et al., 2009). These factors may contribute

toward the potential effects that aggregates have on the

cells.

Figure 6: mHtt aggregates causing accumulation of APC in

cells (Adapted from Bocharova, et al., 2009)

How mHtt protein aggregates can affect proteosomal activity and

may allow an abundance of APC substrates to accumulate in a cell.

Transcription

There is a lot of evidence that mHtt aggregates and the

mHtt protein have an effect on transcription.

Transcription is one of the most important pathways in

the body, as it allows mRNA to be formed for

subsequent creation of proteins. There are different

transcriptional pathways for different proteins in the

body. As the mHtt aggregates would need to be in the

nucleus to have any affect on transcription, they have

to find a way of entry to the nucleus.. There are

already some aggregates in the nucleus (Bocharova et

al., 2009), but cytoplasmic aggregates may have a way

to also enter the nucleus of the cell (Hickey &

Chesselet, 2003). There is a theory that caspases may

be induced by the mHtt aggregates, which may then

cleave the mHtt aggregates (Hickey & Chesselet,

2003). The cleaved aggregates may then be able to

access the nucleus, to affect transcription, through the

nuclear envelope due to its reduction in size (Hickey &

Chesselet, 2003). Aggregates that are cleaved may

actually be toxic to MSNs in the striatum also

(Hackam et al., 1998). Many studies have been done

and have linked mHtt with different transcription

related proteins (Sugars & Rubinsztein, 2003).

Table 2: Transcription factor proteins that interact with mHtt

(Reviewed in Sugars & Rubinsztein, 2003)

Proteins

impaired by

interaction with

mHtt

Proteins that

interact with

mHtt with no

known

consequence

Proteins that

become

impaired but

do not seem to

interact with

mHtt

CBP (CREBBP) mSin3a B-caretin

TAFIII130 TBP (TATABP) CREB

P53 CA150

Sp1 NF-kB: p65 and

p50 subunits

CtBP Dorsal

NCoR

P300

Much transcription related proteins are essential to

different pathways of producing specific proteins (see

table 2). Steffan, Kazantsev, Spasic-boskovic, et al,

(2000) performed experiments using mHtt exon 1

(httex1) to show the relationship of mHtt between p54,

CREBBP (CBP) and mSin3a. p53, also known as

tumor supressor protein 53, is a transcription factor

activator (NCBI, 2013). CBP and mSin3a are both

transcription factors that play a major role in p53

mediated transcription (Steffan, Kazantsev, Spasic-

boskovic, et al., 2000). The results found that httex1

aggregated with p53 in the nucleus both in vitro and in

vivo, and further study had shown that this, in fact,

repressed transcription (Steffan, Kazantsev, Spasic-

boskovic, et al., 2000). Aggregation was also seen

between mSin3a and CBP in vitro. Steffan, Kazantsev,

Spasic-boskovic, et al, (2000) then made the

observation that it was the proline-rich region of the

httex1 which caused the coaggregation with these

transcription proteins. This indicates that httex1 was

mimicking p53 during transcription which might have

caused the repression of transcription. Curiously,

disruptions of another transcription factor, CREB, have

been proven to have a degenerative affect on neurons

in the striatum and hippocampus (Mantamadiotis,

Lamberger, Bleckmann, et al., 2002). Despite all the

evidence of mHtt having an effect on transcription

factors and transcription itself, the idea that mHtt

interactions with transcription causes

neurodegeneration is highly contentious.

Apoptosis and Mitochondrial involvement

There are suggestions that the cause of the MSN cell

death could be due to apoptosis of the cells. Apoptosis

is the programmed death of cells (NCBI, 2002).

Apoptosis and necrosis are the two most common

natural forms of cell death in a body, so it is not

unusual to assume that the HD pathogenesis

mechanism somehow leads to MSN cell apoptosis.

Apoptosis is thought to be instigated by a number of

factors including environmental toxins, metabolic

stress, oxidative stress and excitotoxicity and DNA

damaging agents (Sastry & Rao, 2000). Caspases, such

as caspase 3, caspase 8 and caspase 9, are known to

take part in the mechanism of apoptosis (Sastry & Rao,

2000). Caspase 3 and 9 can act together to initiate

apoptosis (Tang et al., 2005). The mitochondria is

known to have a major role in apoptosis of a cell

(Reviewed in Ferreira, Nascimento, Ribeiro, et al.,

2010).

TUNEL staining is used very commonly to

look for apoptosis in cells (Loo, 2002) and the

technique became useful in HD research. It allows

apoptic cells to be differentiated from normal cells by

a specific stain (Loo, 2002). Many studies involving

apoptosis and HD were done using TUNEL staining

(Tang et al., 2005; Turmaine et al., 2000).

Whether apoptosis is the sole cause of MSN

cell death, there seems to be some contrast in reports.

TUNEL positive, or apoptotic cells, can be present in

HD (Tang et al., 2005). In vitro models of HD have

seen apoptotic cell death in these experiments (Tang,

Slow, Lupu, et al., 2005). It is thought that it may be

glutamate induced apoptosis that causes the MSN cell

death (Tang, Slow, Lupu, et al., 2005). Tang, Slow,

Lupu, et al., (2005) suggest that the mHtt has an affect

on Ca2+ signalling and that leads to the apoptic

mechanism. The proposed mechanism of this

happening is that glutamate stimulates NR1 / NR2B

NMDAR and mGluR5 receptors in the MSNs, and

then the activation of these receptors allows the release

of Ca2+ and InsP3 (inositol triphosphate) from InsP3R

(inositol triphosphate receptor). The mHtt exon would

affect the Ca2+ signalling by making InsP3R1 more

sensitive to InsP3, allowing more NR1 / NR2B

NMDAR, which then causes the mitochondria to take

in more Ca2+ that it can actually hold (Fig. 7). When

the amount of Ca2+ goes past its limit in the

mitochondria, cytochrome c is subsequently released

(Fig. 7) (Tang et al., 2005). Cytochrome c can then

activate caspases (Uniprot, 2007), such as caspase 9

and caspase 3, which in turn, activates the mechanism

of apoptosis (Fig. 7)(Tang, Slow, Lupu, et al., 2005).

This hypothesis would be very plausible because it

also explains the reason for selective

neurodegeneration of MSN as NR1 / NR2B NMDAR

and mGluR5 receptors are present mainly in MSN

(Reviewed in Tang et al., 2005). Conflictingly, a

study done by Ferreira et al., (2010) indicates that it is

not cytochrome c that is involved with the

degeneration process, but AIF (apoptosis inducing

factor) and there may be a degenerative process

involving it.

Figure 7: Hypothesised mechanism for to cause apoptosis to

occur in MSNs (Tang et al., 2005)

Contrary to these studies done indicating that apoptosis

causes neurogeneration of MSN, a study was done

using in vivo and in vitro models of HD, which

indicated that apoptosis was not the cause of cell death

in HD (Turmaine et al., 2000). Turmaine et al., (2000)

used TUNEL staining to try and identify apoptotic

cells but no cells were seen as TUNEL positive. As

well as this, no fragmentation of the nucleus and

cytoplasm; or apoptotic bodies were found in the cells

either (Turmaine et al., 2000).

Other possible causes

Mutant Huntingtin protein also seems to have an affect

the way cells replace themselves, have an excitotoxic

affect on neurons, inflammatory affects and metabolic

pathways in the cell (Reviewed by Ross & Tabrizi,

2011). A major change in some of these processes

could have a detrimental affect on neurons, specifically

medium spiny neurons.

Treatment

Overview

Even with all the information that surrounds

Huntington’s disease, there is still no known cure for

the disease. The only way the sufferers of HD can be

treated at the minute is by using symptomatic

treatments (Adam & Jankovic, 2008) and some

possible therapeutic treatments. There are plenty of

clinical trials ongoing at the moment with regard to

finding symptomatic treatments. Quality of life can be

greatly improved with some symptomatic treatments,

so even if it is not a cure, the HD sufferer, as well as

family and friends, would not have to suffer as much.

Neuroleptics

Neuroleptics are drugs which help prevent psychotic

episodes in HD. There are two main types of

neuroleptics; typical neuroleptics and atypical

neuroleptics (Reviewed by Adam & Jankovic, 2008).

Typical neuroleptics work by having a high affinity on

D2 dopamine receptors, whilst atypical neuroleptics

work by having a higher affinity for 5-HT2A receptors.

Typical neuroleptics are known to treat chorea as well

as psychosis (Bonelli & Hofmann, 2007), but have

more side effects than atypical neuroleptics (Gardner,

Baldessarini & Waraich, 2005). Some examples of

typical neuroleptics include fluphenazine, sulpiride,

haloperidol and pimozide (Reviewed by Adam &

Jankovic, 2008). Some atypical neuroleptics drug

examples are clozapine and olanzapine (Reviewed by

Adam & Jankovic, 2008).

Dopamine depleters

Dopamine depleters can be used as a treatment for

chorea and other movement problems associated with

HD. Some examples of dopamine depleters include

reserpine and tetrabenzine (Adam & Jankovic, 2008).

Tetrabenzine is the more commonly used drug due to

its success rate and the fact that it has less side effects

than reserpine (Reviewed in Adam & Jankovic, 2008).

One of the most severe side effects of these drugs is

depression (Tomlinson, 1977)

Antidepressants

Antidepressants help to alleviate symptoms of

depression. In HD, depression can be a serious

symptom, as mentioned before. Anti-depressants such

as tri-cyclic antidepressants, SSRI’s (selective

serotonin reuptake inhibitors) and SNRI’s (serotonin

norepinephrine reuptake inhibitors) can be used to treat

depression (Medicine, 2013). Fluoxetine may have a

positive effect on chorea, but this is highly disputed

(Reviewed in Adam & Jankovic, 2008).

Therapeutic treatment

There have been studies done on whether therapeutic

target treatment is an effective treatment. The use of

anti-aggregation drugs has been shown to delay

neurodegeneration in a Drosophila model of the

disease (Kazantsev et al., 2002). The prevention of the

cleavage of the mHtt aggregates might help to prevent

mHtt having access to cellular transcription factors,

and therefore possibly inhibiting the disease

(Reviewed in Hickey & Chesselet, 2003).

Latest advances

Lately, a study has been done with regard to

neurodegeneration in prions disease (Moreno,

Halliday, Molloy, et al., 2013). The results of this

study shows a complete stoppage in neurodegeneration

in prions disease in mice with the use of drug called

PERK (protein kinase RNA–like endoplasmic

reticulum kinase) (Moreno, Halliday, Molloy, et al.,

2013). This study might only be seen in prions disease

so far but there is no reason not to believe that the drug

may show the same neuro-protective traits in HD. This

is a first step in what could be a cure for HD.

Conclusion Huntington’s disease is clearly a detrimental disease to

the sufferer, and their family and friends. It seems that

the polyQ repeats are the prime cause of the disease

and that ultimately, MSNs in the brains striatum and

beyond die because of the abnormally long polyQ

repeats. As there are many conflicting reports on the

different possible pathophysiological pathways of HD,

it is extremely difficult to know which one is the

correct neurodegenerative pathway, if any actually are.

It is possible that all of these pathways may occur and

may be part of a major central pathway. As there is the

formation of mHtt aggregates in the disease, it is likely

that these have a major part to play, but it could be that

the aggregates are just a harmless bi-product of another

possible pathophysiological reaction. There is still

copious amounts of research being done into solving

the puzzle that is the pathophysiology of HD. There

are many symptomatic treatments and therapeutic

treatments that can help with the disease but not until a

proven, full pathophysiological mechanism is found

for HD, can finding a cure for the disease be a reality.

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