BS42023 L7

Question 1

what are the triad of symptoms category for HD?

Answer 1

motor, cognitive, psychiatric

Question 2

what are classic symptoms of HD? (4)

Answer 2

tremor, incoordination, stiffness and rigidity

Question 3

describe the stages of disease progression

Answer 3

pre-symptomatic- neurons healthy, high quality of life, no symptoms
prodromal- neurons struggling, declining quality of life, psych/cog symptoms
manifest- neurons dying, severe decline in quality of life, addition of motor symptoms

Question 4

what dominance is the HD gene?

Answer 4

autosomal dominance inheritance- only one copy of the mutant gene needs to be inherited for HD to develop.

Question 5

What is the chance of a child of a carrier inheriting the mutant gene?

Answer 5

100% genetic penetrance

Question 6

where is the Huntington’s protein located?

Answer 6

1st exon of Huntington gene (chromosome 4)

Question 7

what do you have if you’ve inherited HD?

Answer 7

40 or more CAG repeats (codes for glutamine/Q)

Question 8

what number of CAG repeats causes paternal meiotic instability?

Answer 8

29-35 repeats

Question 9

what can modify onset in HD?

Answer 9

environment and other genetics (e.g. FAN1)

Question 10

how can HD aggregates be harmful?

Answer 10

by physically trapping useful molecules in the cell, or overloading the cell’s metabolism as it tries to break them down

Question 11

how are beta-sheets and oligomers formed?

Answer 11

forms hydrogen bonds between itself and other b-sheet monomers to form really strong hair-pin structure

Question 12

what brain structures are lost in HD?

Answer 12

basal ganglia and striatum

Question 13

how does neuron degeneration in D2 pathway contribute to HD symptoms? (6)

Answer 13

• As dopamine D2R containing neurons in the striatum degenerate, the EGP receives less inhibition.
• Since EGP cells are less inhibited they release more neurotransmitters to the STN resulting in higher STN inhibition. Higher inhibition of STN results in less excitatory neurotransmitter release to the IGP.
• IGP neurons become less excited which in turn reduces inhibitory neurotransmission to the thalamus.
• The thalamus receives less inhibition from the IGP.
• This results in increased transmission from the thalamus to the motor cortex, causing over-stimulation.
• This indirect pathway may account for the chorea (uncontrolled tremor) seen early in HD.

Question 14

what type of dopamine neurons die first?

Answer 14

It is believed that striatal cells that project to EGP (indirect pathway, dopamine D2) die before cells that project to the IGP (direct pathway, dopamine D1) hence the time course of chorea and involuntary movement (1st) vs bradykinesia/rigidity/failure of voluntary movement (2nd).

Question 15

what are current preventative therapies for HD?

Answer 15

At present, drugs are used to manage early psychiatric symptoms such as depression and anxiety.
Physiotherapy and occupational therapy are used.
Early motor symptoms (chorea) are treated by tetrabenazine/deutetrabenazine

Question 16

what are some pipeline treatments being developed?

Answer 16

gene silencing, stem cell research

Question 17

how does tetrabenazine work?

Answer 17

• The substantia nigra (upstream of the striatum) releases dopamine and inhibits the striatum D1 and D2 receptor containing neurons modulating activation of the direct and indirect pathways.
• With tetrabenazine, remaining striatal neurons are disinhibited, partially restoring function so the surviving neurons are upregulated and can work harder to inhibit IGP (D1Rs) and EGP (D2Rs).
• Therapy will become less effective as more striatal neurons degenerate (you can’t upregulate what isn’t there)

Question 18

what are the key considerations to treatment with gene silencing ASOs? (5)

Answer 18

1. Getting ASO into the brain- direct injection into the brain; no thanks! (especially since repeated treatments for life). The first clinical trials are using spinal injection into CSF or new Roche Brain Shuttle technology.
2. Distribution: does it need to reach the striatum? (deep structure). Mouse and rat studies find it doesn’t reach deep structures efficiently. Will lowering Htt protein levels somewhere else (e.g. cortex) help anyway?
3. Switch off one or switch off both alleles?: no difference in HD symptom reversal when both WT and mutant alleles were switched off in mice. side effects of switching off WT Htt? (especially developmental)
4. Choosing the right target: target SNPs in mutant Htt that occur in patients? (specific but many possibilities). Target long CAG repeat? (too generic)
5. Side effects: off-target effects- ASO may bind to other mRNA. Immune response.