Huntington's and Parkinson's

Question 1

What are 4 key symptoms of Huntington’s disease?

Answer 1

Cognitive deterioration
Psychiatric impairment
Chorea: abnormal involuntary movement
Dystonia: sustained muscle contraction causing twisting and abnormal postures

Question 2

What is the cause of Huntington’s disease?

Answer 2

Mutation to the huntingtin gene (HTT); has a series of polyglutamine (CAG) repeats, and people with >35 repeats are affected.

This mutation causes a loss of D2 medium spiny neurons in the caudate putamen.

50% chance of transmission to offspring.

Question 3

What is the huntington protein’s normal function? What happens when mutated?

Answer 3

Normal function: transport of organelles and proteins within cell.
- Binds to repressor in cytoplasm to repress BDNF expression.

Mutation:

• Impair transport
• Unable to bind repressor and therefore increase transcription of brain-derived neurotrophic factor (BDNF); this initiates pro-apoptotic signals.

Question 4

What pathway does Huntington’s effect? What is the main function of this pathway?

Answer 4

Nigrostriatal pathway: Dopaminergic SnC neurons project to dorsal striatum and synapse to D2 medium spiny neurons.

Main function is to influence voluntary movement through basal ganglia motor loops.

Question 5

What happens to the basal ganglia pathways in Huntington’s?

Answer 5

The projection from the dorsal striatum (caudate putamen) is diminished.

This increases inhibition of the subthalamic nucleus by the external globus pallidus, making the excitatory subthalamic nucleus less effective in opposing the direct pathway.

This leads to expression of unwanted motor activity.

Question 6

What does the brain look like with Huntington’s?

Answer 6

The dorsal striatum is very shrunk as D2 neurons die.

The cortex is also shrunk as neurodegeneration spreads.

Question 7

What is the excitotoxicity hypothesis?

Answer 7

NMDA receptors are highly permeable to Ca2+, and high levels of Ca2+ can be damaging to the brain.

One study found excessive NMDA activity kills neurons by excitotoxicity and caused degeneration in rat striatum MSNs. This indicates that excitotoxicity may be a mechanism of neurodegeneration in Huntington’s disease.

Question 8

What did Milnerwood and Raymond observe about spontaneous AMPA currents of Huntington’s mice?

Answer 8

• AMPA sEPSCs have a quicker time constant in HTT mice.
• HTT mice have a greater number of # of smaller-amplitude sEPSCs for AMPA.
• There were no changes in frequency.

Question 9

What did Milnerwood and Raymond observe about evoked AMPA currents of Huntington’s mice?

Answer 9

• In HT mice, paired-pulse facilitation showed impaired probability of neurotransmitter release. They concluded that MSNs of HTT mice have dysfunctional NT release probability.
• HTT mice are also less able to maintain response to prolonged stimulation.
• Amplitudes of AMPA eEPSCs were significantly reduced.

Question 10

What 2 reasons did Milnerwood and Raymond give to explain why amplitudes of AMPA eEPSCs significantly reduced?

Answer 10

1) Decreased neurotransmitter release

2) Decreased amount of postsynaptic AMPA

Question 11

What did Milnerwood and Raymond observe about evoked NMDA currents of Huntington’s mice?

Answer 11

• No change in NMDA amplitude.
• Increase in NMDA:AMPA current relationship in HTT mice; increased NDMA contribution to synaptic transmission.
• Increase in time constant (longer to decay)
• No difference in Mg2+ block sensitivity.