Neurodegeneration Five - Huntingtons

Question 1

What is the htt protein used for?

Answer 1

• Transport

- antiapoptotic functions

Question 2

What happens to mutant htt?

Answer 2

accumulations of the protein are called inclusions and these are heavily ubiquitinated(small protein attatched to it) - identifiable

Question 3

In huntingtons do dying cells have inclusions?

Answer 3

Most dying cells and neurons do not have inclusions

Question 4

Whats a macroscopic observation of huntingtons?

Answer 4

Marked cerebral atrophy

Question 5

Whats some microscopic observations of huntingtons?

Answer 5

• Neurons that use gaba are preferentially affected

- Medium spiny neurons

Question 6

Can huntingtons be inherited?

Answer 6

It is autosomal dominant (yes) therefore it depends on the number of CAG repeats as to dominance 40+ is full penetrance

Question 7

On a genetic level what causes huntingtons?

Answer 7

expanded CAG region (codes for glutamate)

Question 8

where is the htt gene located?

Answer 8

IT15 in the short arm of chromosome 4

Question 9

whats the corrolation between CAG repeats and disease?

Answer 9

up to 35 = normal (20 is normal)
35-40 = gene carrier
40+ = full penetrance and HD

Question 10

Whats the incidence of HD?

Answer 10

5 in 100,000 in NZ

Question 11

When does HD onset?

Answer 11

Depends on the extent of CAG repeats as to its insensity and onset, but typically 35-45years

Question 12

What are the symptoms of HD?

Answer 12

• Hyperkinesia/rigidity
• CHOREA (Involuntary movements) - extrapyramidal movements
• Behavioural and cognition changes (first symptom)
• Athetosis (bodies midline is displaced)

Question 13

Is htt asymetric?

Answer 13

It is a disease of the basal ganglia in boths hemispheres

Question 14

What do basal ganglia control?

Answer 14

Mood and movement

Question 15

Does chorea occur in sleep?

Answer 15

No

Question 16

What does the loss of medium spiny nuerons lead to?

Answer 16

GPi neurons are tonically active

Question 17

Is there a sequence of cell loss in the basal ganglia?

Answer 17

Yes

Question 18

What is the cell loss sequence?

Answer 18

medium spiny gaba neurons are preferentially lost starting with:
1) Striatum - GPe loss
= Loss of gaba, decreased inhibition of thalamus, hyperkinesia
2) Striatal - nigral neurons are loss
3) Straital - GPi neurons lost
= loss gaba (GPI), increased inhibition of thalamus = rigidity

Question 19

What does number of CAG repeats correlate with?

Answer 19

• Age of onset, intensity and pathology

Question 20

Whats the treatment for htt?

Answer 20

No drugs work

• can relieve some symptoms i.e antidepressants
• gene therapy
• neural tranplants

Question 21

Is either gender preferentially affected?

Answer 21

No

Question 22

What is htt associated with?

Answer 22

Genetic anticipation

Question 23

What is genetic anticipation?

Answer 23

Some repeats are inherited

• Mum = ~4
• Dad = up to 7
• Paternal age = longer repeats, due to the quality of sperm and eggs

Question 24

What neurons are lost first in htt?

Answer 24

Gaba MSN projecting from the striatum to the GPe thus the indirect pathway (via SNT) becomes tonically active (no inhibiton)

Question 25

Whats the vonsattle grading?

Answer 25

0 = minimal overt change
1 = 50% loss neurons in cns
2-3 = major loss of neurons
4 = 95% loss of neurons in the CNS

Question 26

Whats an early sign the HD is on the way?

Answer 26

Loss of CB1 receptors in the CNS

Question 27

Learn the diagram

Answer 27

NOw