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Neurodegenerative > Huntingtons > Flashcards

Huntingtons Flashcards

1
Q

What is HD?

A

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

Prognosis usually 15-20 yrs from onset of symptoms

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2
Q

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

A

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

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3
Q

Prevalence of HD

A

Increasing
Higher prevalence in America, Europe, Australia etc

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4
Q

Faulty gene in HD

A

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

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5
Q

10-30 CAG repeats (poly glutamine repeats)

A

Normal HTT gene

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6
Q

36+ repeats of CAG (polyglutamine tail)

A

Diseases HTT gene

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7
Q

Poly-Q expansion and anticipation

A

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

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8
Q

Age of onset of HD

A

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)

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9
Q

Clinical progression

A

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

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10
Q

2 phases of HD

A

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

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11
Q

Symptoms of HD

A

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

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12
Q

Symptoms: physical

A

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

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13
Q

Symptoms: cognitive

A

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

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14
Q

Normal function of basal ganglia

A

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

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15
Q

Neuropathology of HD (basal ganglia)

A

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

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16
Q

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

A

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

17
Q

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

A
18
Q

Medium spiny neurone

A

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

19
Q

Neuropathology progression (grades)

A

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

20
Q

HD aggregates: enriched in N terminal fragments

A

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

21
Q

Inclusion bodies

A

Insoluble protein aggregation
>40Qs

22
Q

Loss of function (LOF)

A

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)

23
Q

Gain of function (GOF)

A

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

24
Q

Pathological roles of mtHTT protein

A

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

25
Q

MtHTT and transcriptional machinery

A

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

26
Q

Loss of function example

A

Normal HTT removes REST allowing transcription of gene eg BDNF

MuHTT cannot remove REST

27
Q

Gain of function example

A

inhibition of CREB dependent transcription (inhibition of CBP)

28
Q

Can Mutant huntingtin regulate epigenetic changes

A

Yes
Can cause changes in DNA
Through inhibition deacetylases

GAIN OF FUNCTION

29
Q

Mitochondrial dysfunction and HD

A

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

30
Q

Anti-apiptotic (IAP) activity lost

A

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

31
Q

Degeneration by dying back

A

Neurone degeneration starting from axonal projection

32
Q

Why are medium spiny neurones more susceptible to degeneration

A

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

33
Q

Huntington mediated dysfunction

A

Transport deficits
Transmitter release deficits
Ca2+ homeostatsis issues
Proteosomal dysfunction
Signalling dysfunction

(Autophagy - protein and membrane clearance)

34
Q

Properties of neurones that are relatively susceptible

A

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

35
Q

Treatments for HD

A

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

36
Q

Therapeutic targets/strategies

A

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

37
Q

ASO (Antisense oligonucleotides)

A

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

Neurodegenerative (8 decks)

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