Huntington's Disease - Mechanisms

Question 1

In which year was the first animal model of HD created?

Answer 1

1976

Question 2

When was the HD gene identified?

Answer 2

1983

Question 3

Where is the mutation in Huntingtons?

Answer 3

Chromosome 4

Question 4

What is the penetrance of the Huntingtons mutation?

Answer 4

100%

Question 5

CAG repeats can creep closer to the HD threshold in which sex?

Answer 5

Females

Question 6

What does the mutation in HD code for?

Answer 6

Glutamine Q

Question 7

What is the abnormally long CAG repeat region translated to?

Answer 7

Abnormally long polyglutamine tracts in the Htt protein

Question 8

What is the relationship between number of repeats and age of onset?

Answer 8

More repeat, earlier age of onset

Question 9

Which areas are most susceptible to neuronal cell death in HD?

Answer 9

Basal ganglia and cortex

Question 10

What effect does the mutation have on Htt?

Answer 10

Makes it more likely/easier to aggregate

Question 11

What is the main function of Htt?

Answer 11

Unknown

Question 12

What happens in Htt KO mice?

Answer 12

Die

(But if switch off later in life, survives)

Question 13

Where is the highest expression of Htt?

Answer 13

Brain and testes

Question 14

Give examples of motor symptoms

Answer 14

Chorea
Dystonia
Motor impersistence
Impaired gait/balace
Delayed initiation of voluntary saccades

Question 15

Give examples of cognitive symptoms

Answer 15

Loss of executive function
Difficulty multitasking
Rigid/inflexible thoughts
Impaired spatial perception and impulsive control
Deprecation of vocabulary 
Short term memory loss

Question 16

Give examples of psychiatric symptoms

Answer 16

Depression
Hallucinations
Paranoia
Irritability

Question 17

Outline the indirect pathways.

Answer 17

Motor cortex excites striatum
Striatum inhibits EGP
EGP then exhibits less inhibition on the STN
This lifts inhibition of the IGP
IGP then free to act and inhibit the thalamus to stop movement

Question 18

Which part of the indirect pathway is damaged in HD?

Answer 18

Betw the striatum and the EGP

Question 19

Outline the abnormal indirect pathway functioning in HD

Answer 19

Striatum cant inhibit the EGP.
More EGP activity so even inhibition of the STN
This means less activation

Question 20

Outline the direct pathway

Answer 20

Cerebral cortec excites the striatum
The striatum sends inhibitory projection to the IGP
The IGP then cant send inhibitory signal to the thalamus
The thalamus is free to excite the motor cortex

Question 21

Which pathways degenerates first?

Answer 21

Indirect (because d2 neurons degenerate before d1)

Question 22

Where is the damage in the direct pathway?

Answer 22

Between the striatum and the IGP

Question 23

Outline the abnormal functioning of the direct pathway in HD

Answer 23

Striatum unable to inhibit IGP
IGP is disinhibited and therefore increased inhibition of the thalamus
Less movement

Question 24

Who originally put forward the idea that many disorders may be caused by the general concept of abnormal folding and unfolding of proteins?

Answer 24

Carrell and Lomas

Question 25

How may proteotoxicity be suppressed in misfolding?

Answer 25

Suppressing the initial oligomerisation of the disease proteins and promoting their degradation

Ubiquitin degradation

Mayo et al 2015

Question 26

How may mutant Htt induce cytotoxic cell death?

Answer 26

Induces oxidative and metabolic stress in by affecting mitochondrial function
Increases susceptibility to membrane excitability - lead to excitotoxicity
Causes cell body inclusions but pathological role unclear
Sawa et al 2003

Decreases protein degradation in cells (potentially by increasing half life)
Increases RTP801 expression (this is proapoptotic)
Alberch et al 2015