Huntingtons

Question 1

What is HD?

Answer 1

Autosomal dominant, heredity, neurodegenerative disease
Characterised by cognitive, behavioural and motor dysfunction

Prognosis usually 15-20 yrs from onset of symptoms

Question 2

Pedigreed of HD if one parent has Huntington’s (Hh)

Answer 2

1) everyone with mutated gene will get HD
2) 50% chance of each offspring inheriting affected gene
3) inheritance is independent of gender

Question 3

Prevalence of HD

Answer 3

Increasing
Higher prevalence in America, Europe, Australia etc

Question 4

Faulty gene in HD

Answer 4

HTT
Poly glutamine tail (CAG) (length responsible for HD)

Question 5

10-30 CAG repeats (poly glutamine repeats)

Answer 5

Normal HTT gene

Question 6

36+ repeats of CAG (polyglutamine tail)

Answer 6

Diseases HTT gene

Question 7

Poly-Q expansion and anticipation

Answer 7

Offspring inherits AT LEAST the same amount of repeats as parents but can be more
More likely to have more mutations so more likely to have HD with each generation
More repeats means the more severe and earlier onset of disease
Parent doesn’t have disease, child does = sporadic

Question 8

Age of onset of HD

Answer 8

Strong inverse relationship between age of onset and number of CAG repeats
Normal - 26 or less
Intermediate - 27-35 (their children risk having HD)
Reduced penetrance - 36-39 (disease usually at older age) (LATE ONSET)
Full penetrance - 40+ (30-50yrs old)
60+ (JUVENILE MANIFESTATION)

Question 9

Clinical progression

Answer 9

Prodomal - chorea biggest increase then cognitive, the motor
Manifest - motor impairments biggest then cognitive then chorea

Question 10

2 phases of HD

Answer 10

Phase 1) neurones, signalling and connectivity affected
Phase 2) death of neurones (motor impairment seen)

Question 11

Symptoms of HD

Answer 11

1) movement: voluntary and involuntary
2) behaviour: changes in behaviour and personality
3) cognitive: difficulties with planning and thinking

Symptoms may be present while before diagnosis, misdiagnosis eg PD or AD
Movement usually first symptoms
Behavioural most concerning

Question 12

Symptoms: physical

Answer 12

Jerking/ Fidgety motor deficits
Clumsiness
Slurred speech
Abnormal eye movements
Swallowing issues
Weight loss
Involuntary movements
Incontinence

Question 13

Symptoms: cognitive

Answer 13

Memory and concentration issues
Lack of motivation
Can’t plan and think ahead
Emotional changes
Reduced ability to read facial expressions
Aggression, demanding, self centred
Impulsive and irrational

Question 14

Normal function of basal ganglia

Answer 14

Cortex activity increases
Glutamate released onto putamen
Putamen activity increases
Release of GABA onto globus pallidus
Decreased activity of globus pallidus
Less GABA released by globus pallidus
Excitation of thalamus
Activated motor cortex
Activation of muscles and control of movement

Question 15

Neuropathology of HD (basal ganglia)

Answer 15

Degeneration of putamen
Less inhibitory activity of putamen
Less inhibition of globus pallidus
So thalamus inhibited by release of GABA
So less activation of motor cortex
So less activation of muscles and control of movement

Question 16

Features of neurones selectively susceptible to degeneration in HD - direct pathway

Answer 16

Cortex, putamen, globus pallidus, thalamus, motor cortex, muscle/movement

Question 17

Features of neurones selectively susceptible to degeneration in HD - indirect pathway (EXTRA READING)

Question 18

Medium spiny neurone

Answer 18

Main and earliest striatal cell type affected in HD

Spiny striatal neurones - GABAergic, degeneration of these so loss of these loss of GABA function

Aspiny striatal neurones - unaffected

Question 19

Neuropathology progression (grades)

Answer 19

Grade 0/1 - indistinguishable from normal brain. Selective neuronal loss in caudate and putamen of striatum Upton histological examination

Grade 2 - enlargement of lateral ventricle. Loss if cortico-striatal projection neurones. Severe striatal atrophy

Grade 3/4 - severe HD cases. Atrophy if striatum and wide cell loss in cortical, cerebellum, hippocampal and hypothalamic regions

Question 20

HD aggregates: enriched in N terminal fragments

Answer 20

Full length huntingtin makes stable protein
Longer Poly-Q hungtinin tail makes unstable/misfolded protein causing and dysfunctional cellular pathways causing disrupted proteostasis creating abnormal conformations, intracellular aggregates, beta sheet structures and inclusion bodies

Question 21

Inclusion bodies

Answer 21

Insoluble protein aggregation
>40Qs

Question 22

Loss of function (LOF)

Answer 22

Mutant protein no longer able to perform normal functions
Occurs when there is a mix of normal and mutant protein (eg modifying protein interaction making them weaker so binding lost)

Question 23

Gain of function (GOF)

Answer 23

Extra activating imparted by mutant protein (eg expanded plyQ creates protein comforters which are toxic; create new activity/interactions - albeit dysfunctional)

Question 24

Pathological roles of mtHTT protein

Answer 24

1) HTT translation
2) proteolytic cleavage
3) nuclear translocation
4) nuclear oligomization and aggregation & intracellular inclusion so dysregulated transcription
5) protein aggregation
6) impairment of proteastasis network

Question 25

MtHTT and transcriptional machinery

Answer 25

Inhibition of transcription (75%) Inhibits Histone modifications, reducing transcription of genes by inhibiting CBP and so controlling CRE (acetylation enzymes) Examples: inhibition of CREB dependent transcription (CBP) GAIN OF FUNCTION

Question 26

Loss of function example

Answer 26

Normal HTT removes REST allowing transcription of gene eg BDNF MuHTT cannot remove REST

Question 27

Gain of function example

Answer 27

inhibition of CREB dependent transcription (inhibition of CBP)

Question 28

Can Mutant huntingtin regulate epigenetic changes

Answer 28

Yes Can cause changes in DNA Through inhibition deacetylases GAIN OF FUNCTION

Question 29

Mitochondrial dysfunction and HD

Answer 29

Gain of function Aggregation of hungtinini = mitochondrial dysfunction through pore opening Enhanced sensitivity of mPTP to ca2+ leading to apoptosis of cell due to: reduced membrane potential, decreased ca2+ buffering capacity and increase in ROS production

Question 30

Anti-apiptotic (IAP) activity lost

Answer 30

Loss of function Normal HTT blocks procaspase -9 by direct binding Procaspase -9 not blocked my muHTT so increased sensitivity

Question 31

Degeneration by dying back

Answer 31

Neurone degeneration starting from axonal projection

Question 32

Why are medium spiny neurones more susceptible to degeneration

Answer 32

Exposed to high levels of glutamate cellular depolarisation (neurotoxic) High firing rates, high metabolic remains Long projection axon, dependent on efficient transport Selective expression of neuro peptides, ca2+ binding proteins

Question 33

Huntington mediated dysfunction

Answer 33

Transport deficits Transmitter release deficits Ca2+ homeostatsis issues Proteosomal dysfunction Signalling dysfunction (Autophagy - protein and membrane clearance)

Question 34

Properties of neurones that are relatively susceptible

Answer 34

No common biochem characteristics among main neuronal pops effected by HD Increased vulnerable if neurons with longer and more prominent axons

Question 35

Treatments for HD

Answer 35

All targeted at alleviating symptoms Chorea - tetrabenasine (FDA approved), ziprasidone Depression - citalopram/fluoxetine Anxiety - lozazepam Muscle tremors - clonazepam Cognitive dysfunction- donepezil

Question 36

Therapeutic targets/strategies

Answer 36

Prevent muHTT regulating system deactylases so kinase inhibition and GM1 Autophagy enhancers and chaperone enhancers KMO inhibition, immunomodulation HTT loading (ASO or RNAi)

Question 37

ASO (Antisense oligonucleotides)

Answer 37

Allele selective drugs, bind to and target for degradation, muHTT mRNA via single nucleotide polymorphisms So gene silencing Halted in phase 3 because of safety concerns Deliver through striatum or spinal fluid etc