Lecture 7: Huntington and Parkinson's

Question 1

Most obvious huntington’s disease symptoms?

Answer 1

Chorea: abnormal body movements and lack of coordination
autosomal dominant disease: only requires one affected allele from either parent to inherit

Question 2

Which chromosome does the abnormal Htt gene located?

Answer 2

chromosome 4

Question 3

the abnormal huntington gene have how many CAG repeats?

Answer 3

more than 36
if more than 39 definitely pathogenic

Question 4

Medium-sized spiny neurons

Answer 4

receive dopaminergic output from midbrain
secrete GABA
loss of spiny neurons results in decreased inhibition of the thalamus
cause increase output to other regions of the brain’s cerebral cortex
lead to chorea

Question 5

2 Pathological hallmark of Parkinson’s

Answer 5

1. degeneration of dopaminergic neuron at substantia nigra (SN)
2. presence of lewy bodies formed in major part by deposits of alpha-synuclein and ubiquitin

Question 6

What is MPTP?

Answer 6

by product of MPPP synthesis (synthetic opioid analog of demerol)
used to induce parkinson’s

Question 7

How does MPTP cause parkinsonism?

Answer 7

MPTP convert to toxic MPP+ by monoamine oxidase (MAO-B)
Uptaken by DAT and accumulate in neuron
inhibit complex I of the electron transport chain

Question 8

How does VMAT2 affect MPP+ levels?

Answer 8

more VMAT2 can facilitate uptake of MPP+ into vesicle, less MPP+ can reach mitochondria and inhibit complex I

Question 9

Deprenyl

Answer 9

MAO-B inhibitor, prevent MPTP conversion to MPDP+, prevent MPP+ toxicity

Question 10

GBR 12909

Answer 10

dopamine reuptake inhibitor, inhibit dopamine transporter, prevent uptake of MPP+ into neuron

Question 11

L-DOPA (levodopa)

Answer 11

intermediate and rate limiting step in dopamine biosynthesis
PRODRUG to increase dopamine levels
can cross BBB by itself through active transport, dopamine cannot
metabolized to dopamine by dopa decarboxylase

Question 12

Adverse effect of L-DOPA

Answer 12

hypotension
arrhythmias
GI upset

L-Dopa induced dyskinesia

Question 13

Carbidopa and Benserazide

Answer 13

dopamine decarboxylase inhibitor
prevent peripheral metabolism of L-Dopa to dopamine
increase L-Dopa transfer to BBB
require lower dose of L-Dopa if administered

Question 14

alpha-Methyl-P-tyrosine (a-MPT)

Answer 14

mediate synthesis from TH to dopamine
if blocked depletes dopamine in DAT knockouts because no recycling of dopamine