Huntington's Disease

Question 1

What are the symptoms of adult-onset HD?

Answer 1

Chorea - involuntary jerky movements
Loss of voluntary movement control
Gait and balance problems
Delayed saccades
Psychiatric symptoms (e.g. depression, psychosis)
Cognitive symptoms
Weight loss

Question 2

What type of inheritance pattern does HD have?

Answer 2

Autosomal dominant

Question 3

Which gene is mutated in HD?

Answer 3

HTT

Question 4

How many CAG repeats does the normal allele have?

Answer 4

1-26

Question 5

How many CAG repeats does the high normal allele have and what is the effect of this?

Answer 5

27-35
Neurological problems - but not HD -
Can expand in future generations - but no HD risk to individual

Question 6

How many CAG repeats does the reduced penetrance allele have and what is the effect of this?

Answer 6

36-39

Some do not develop HD - may be due to death before symptom presentation - limited by human lifespan

Question 7

How many CAG repeats does the abnormal allele have and what is the effect of this?

Answer 7

40+

Complete penetrance - causes HD

Question 8

What is the relationship between CAG repeat length and age of HD onset?

Answer 8

Increased repeat length - decreased age of onset

Question 9

What is anticipation?

Answer 9

More CAG repeats down generations

More severe and earlier disease onset down generations

Question 10

How does anticipation occur?

Answer 10

DNA replication machinery slips back

Replicates same stretch of CAG repeats more than once

Question 11

How many CAG repeats are required for the mutant huntingtin with a different conformation to the WT?

Answer 11

36+

Question 12

What is likely to be the purpose of the hole in huntingtin?

Answer 12

Fit DNA within

Question 13

Name 4 physiological roles of huntingtin

Answer 13

Endocytosis
BDNF trafficking
Autophagy
Transcriptional regulation - via direct DNA interaction

Question 14

What is the effect of huntingtin KO in mice?

Answer 14

Lethal

Question 15

What are the species of huntingtin and which is the most toxic?

Answer 15

Soluble fibrils - most toxic

Insoluble aggregates

Question 16

What are the effects of cytoplasmic huntingtin aggregates?

Answer 16

Impair proteostasis (e.g. autophagy) - toxic proteins accumulates
Sequester chaperones - hinders protein folding

Question 17

How is the translocation huntingtin poly(Q) sequence altered in HTT mutants and what is the effect of this?

Answer 17

Poly(Q) sequence returns to nucleus

Forms insoluble nuclear aggregates - disrupt transcription

Question 18

In which cell type is cell death most prominent in HD?

Answer 18

GABAergic MSNs of striatum

Question 19

Which brain areas are affected by atrophy in HD?

Answer 19

All except cerebellum

Question 20

How do the symptoms of juvenile HD differ from those of adult-onset HD?

Answer 20

No chorea

Seizures

Question 21

What are the cognitive symptoms of HD?

Answer 21

Impulsivity
Irritability
Normal memory

Question 22

When do the cognitive symptoms of HD present?

Answer 22

≥10yrs before motor symptoms

Question 23

What is the effect of expressing only exon 1 of HTT in mice?

Answer 23

HD model - falls off rotarod, dies early

Question 24

How was it previously thought that huntingtin exon 1 fragment was formed?

Answer 24

Huntingtin cleaved - to toxic exon 1 protein

Question 25

How is it now thought that huntingtin exon 1 fragment is formed?

Answer 25

Aberrant splicing of HTT pre-mRNA | Excess CAG repeats in HTT predispose to early snipping - by affecting intron 1 splicing signals

Question 26

What is the effect of germline instability on HTT?

Answer 26

Intergenerational CAG repeat number changes

Question 27

What is the effect of somatic instability on HTT?

Answer 27

In some tissues repeat length increases during lifespan (e.g. striatum MSNs) Can be different CAG repeat length in different tissues

Question 28

Which type of gene can modify HD onset and why?

Answer 28

DNA repair genes | DNA repair affects somatic instability

Question 29

Which factor do striatal MSNs require for survival?

Answer 29

BDNF

Question 30

Where is BDNF made and how is it transported to striatal MSNs?

Answer 30

Made in cortical cell bodies | Transported down corticostriatal axons

Question 31

How is BDNF affected in HD?

Answer 31

Decreased production | Less efficient trafficking - due to role of huntingtin in trafficking

Question 32

How do ASOs affect HTT?

Answer 32

Bind to HTT pre-mRNA Destroy Prevent HTT protein synthesis

Question 33

What was the effect of an HTT ASO in a human trial?

Answer 33

Decreased exon 1 mHTT protein in CSF No serious side effects Correlation between degree of mHTT protein decrease and clinical score change

Question 34

Name 2 future possible treatments for HD and what they target

Answer 34

RNAi - mHTT mRNA - prevent translation | Zinc finger proteins - HTT DNA - cut mutation out

Question 35

What is a possible problem with the current HTT ASO?

Answer 35

It blocks production of mutant and WT huntingtin