L53 - Molecular basis of neurological disease I - Huntington's

Question 1

Describe the etiology of Huntington’s?

Answer 1

Inherited neurodegenerative disorder

Monogenic autosomal dominant: Abnormal huntingtin gene (male to female affected equally)

Highly penetrant, typically begins in mid-life (age 30-45)

Question 2

List some motor disorder of Huntington’s?

Answer 2

 Chorea (dance-like movements) 
 Gait abnormalities  
 Incoordination 
 Dysarthria (impairment of speech muscles)  
 Eye movement abnormalities 
 Rigidity / bradykinesia / dystonia

Question 3

List some cognitive disorder of Huntington’s?

Answer 3

Subcortical dementia: 
 Frontal type problems: impaired executive functions (problem-solving, planning etc.) 
 Mental slowing 
 Poor attention 
 Memory difficulties

+ late stage global dementia
+ depression

Question 4

List some psychiatric disorder of Huntington’s?

Answer 4

 Personality change (apathy, irritability, disinhibition, emotionally labile)
 Mood swings
 Social withdrawal
 Poor self-care, alcoholism

Question 5

Describe the progression of clinical presentation in Huntington’s disease?

Answer 5

Early:
•progressive emotional, psychiatric and cognitive disturbances

Intermediate:
•motor signs
•progressive dementia

Late:
•unable to walk 
•poor dietary intake 
•aspiration pneumonia
•long term institutional care

Question 6

Describe which brain regions are affected by Huntington’s?

Answer 6

Neostriatal atrophy

– prominent neuronal loss of medium spiny neurons (GABAergic) in striatum (caudate, putamen)

Question 7

Describe the length, locus and expression of normal huntingtin gene?

Answer 7

> 200,000 base pairs, 67 exons = Large 348kDa protein

Locus = chromosome 4p

Normally contains 20-30 repeats of Polyglutamine (polyQ) sequence (CAG repeats)

Expression = widespread inside cell, with lots of functions (clathrin-coated vesicles, endosomal compartment, microtubule)

Question 8

Pathogenesis of Huntington’s?

Answer 8

Single mutation in Htt gene

> > Expansion of CAG repeats in 1st exon ( >36 CAG repeats)

> > Abnormal htt with abnormal elongated polyG region

> > unfolding / abnormal folding inhibits proteasome degradation

> > accumulate in cytoplasm of neurons and cause widespread damage + loss of normal huntington’s cause massive neuronal death

Question 9

List the 4 effects of abnormal huntington gene accumulation in cells? (think about which intracellular organelle/ pathways are affected)

Answer 9

1. Impair calcium signaling and homeostasis
2. Mitochondrial dysfunction
3. Impair gene transcription of BDNF (protective factor)
4. Alter vesicular transport and recycling of neurotransmitters

Question 10

How does the amount of CAG repeats in abnormal Htt gene dictate the onset of disease?

Answer 10

HD patients: >36 CAG repeats

 36-38 = significant
 >39 = definitely pathogenic

large number of repeats = develop symptoms at an earlier age

Question 11

MoA and name of one candidate drug that can treat Huntington’s?

Answer 11

AMT130

MoA: AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the mutant huntingtin gene