HD Genetics - Cormier

Question 1

Why is HD actually a good target for possible future genetic therapy?

Answer 1

One single cause in ALL patients!

Question 2

What is the penetrance of HD?

Answer 2

100% with anyone having over 40 CAG repeats!

Question 3

How is the number of polyQ related to severity?

Answer 3

Directly relatedunder 35 normal
36-41 incomplete penetrance
40-60 adult onset
60+ juvenile onset

Severity also increases with earlier onset

Question 4

Does ApoE allele have any connection?

Answer 4

Yes.
E4 = protective
E2/3 = lowers age of onset

Question 5

Does gender affect anything?

Answer 5

Inheriting the disease from the father actually increases the severity and lowers age of onset

Males just have a higher gamete mutation rate than women

Question 6

Can you do anything behaviorally to change your risk?

Answer 6

omega 3 = protective (fish)
Omega 6 = hurts (red meat)

Intellectual stimulation = protective

Question 7

Why does the HTT protein cause problems as a PolyQ mutant?

Answer 7

• The HTT protein is a substrate for protease cleavage
• Expanded polyQ in exon 1 enhances the rate of cleavage at a nearby site
• Cleaved wildtype HTT would be degrade in the cytoplasm
• Cleaved mutant HTT actually goes to the nucleus where it is trapped and forms protein aggregates

Question 8

Are nuclear inclusions pathogenic or protective?

Answer 8

Not understood currently

Could be either

Question 9

Main cellular mechanism of neurotoxicity from HD?

Answer 9

(1) dysregulation of transcription caused by toxic nuclear aggregates
(2) altered neurotransmitters & excitotoxicity
(3) interference with wildtype Htt: changes in axonal transport & synaptic function
- apoptosis
- oxidative stress related to mitochondrial dysfunction

Question 10

2 ways that huntingtin can dysregulate normal transcription?

Answer 10

Can trap various trasncription factors

Can inhibit histone acetylase and repress transcription

Question 11

Where along the corticostriatal pathway might dysfunction cause the excitotoxicity contributing to HD?

Answer 11

• Increased Glu release from afferent
• Reduced uptake of Glu by glial cells
• Hypersensitivity of Post-synaptic NMDA receptors
• Altered Ca homeostasis
• Mitochondrial dysfunction in postsynaptic cell

Question 12

Why would the simple interference of wild-type HTT contribute to HD?

Answer 12

WT
-involved in many neuronal functions
(vesicle trans., endocytosis, synpase fucntions.)
-anti-apoptotic

Question 13

How does oxidative stress occur in HD?

What does it do?

Answer 13

• Excitotoxicity causes large amounts of intracellular Ca to be released
• This interferes with mitochondrial function
• Cytochrome C/Caspase cascade activated!
• Cell death!