Huntington's Disease Flashcards
What are the symptoms of adult-onset HD?
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
What type of inheritance pattern does HD have?
Autosomal dominant
Which gene is mutated in HD?
HTT
How many CAG repeats does the normal allele have?
1-26
How many CAG repeats does the high normal allele have and what is the effect of this?
27-35
Neurological problems - but not HD -
Can expand in future generations - but no HD risk to individual
How many CAG repeats does the reduced penetrance allele have and what is the effect of this?
36-39
Some do not develop HD - may be due to death before symptom presentation - limited by human lifespan
How many CAG repeats does the abnormal allele have and what is the effect of this?
40+
Complete penetrance - causes HD
What is the relationship between CAG repeat length and age of HD onset?
Increased repeat length - decreased age of onset
What is anticipation?
More CAG repeats down generations
More severe and earlier disease onset down generations
How does anticipation occur?
DNA replication machinery slips back
Replicates same stretch of CAG repeats more than once
How many CAG repeats are required for the mutant huntingtin with a different conformation to the WT?
36+
What is likely to be the purpose of the hole in huntingtin?
Fit DNA within
Name 4 physiological roles of huntingtin
Endocytosis
BDNF trafficking
Autophagy
Transcriptional regulation - via direct DNA interaction
What is the effect of huntingtin KO in mice?
Lethal
What are the species of huntingtin and which is the most toxic?
Soluble fibrils - most toxic
Insoluble aggregates
What are the effects of cytoplasmic huntingtin aggregates?
Impair proteostasis (e.g. autophagy) - toxic proteins accumulates Sequester chaperones - hinders protein folding
How is the translocation huntingtin poly(Q) sequence altered in HTT mutants and what is the effect of this?
Poly(Q) sequence returns to nucleus
Forms insoluble nuclear aggregates - disrupt transcription
In which cell type is cell death most prominent in HD?
GABAergic MSNs of striatum
Which brain areas are affected by atrophy in HD?
All except cerebellum
How do the symptoms of juvenile HD differ from those of adult-onset HD?
No chorea
Seizures
What are the cognitive symptoms of HD?
Impulsivity
Irritability
Normal memory
When do the cognitive symptoms of HD present?
≥10yrs before motor symptoms
What is the effect of expressing only exon 1 of HTT in mice?
HD model - falls off rotarod, dies early
How was it previously thought that huntingtin exon 1 fragment was formed?
Huntingtin cleaved - to toxic exon 1 protein
How is it now thought that huntingtin exon 1 fragment is formed?
Aberrant splicing of HTT pre-mRNA
Excess CAG repeats in HTT predispose to early snipping - by affecting intron 1 splicing signals
What is the effect of germline instability on HTT?
Intergenerational CAG repeat number changes
What is the effect of somatic instability on HTT?
In some tissues repeat length increases during lifespan (e.g. striatum MSNs)
Can be different CAG repeat length in different tissues
Which type of gene can modify HD onset and why?
DNA repair genes
DNA repair affects somatic instability
Which factor do striatal MSNs require for survival?
BDNF
Where is BDNF made and how is it transported to striatal MSNs?
Made in cortical cell bodies
Transported down corticostriatal axons
How is BDNF affected in HD?
Decreased production
Less efficient trafficking - due to role of huntingtin in trafficking
How do ASOs affect HTT?
Bind to HTT pre-mRNA
Destroy
Prevent HTT protein synthesis
What was the effect of an HTT ASO in a human trial?
Decreased exon 1 mHTT protein in CSF
No serious side effects
Correlation between degree of mHTT protein decrease and clinical score change
Name 2 future possible treatments for HD and what they target
RNAi - mHTT mRNA - prevent translation
Zinc finger proteins - HTT DNA - cut mutation out
What is a possible problem with the current HTT ASO?
It blocks production of mutant and WT huntingtin