Huntingtons Flashcards
What is HD?
Autosomal dominant, heredity, neurodegenerative disease
Characterised by cognitive, behavioural and motor dysfunction
Prognosis usually 15-20 yrs from onset of symptoms
Pedigreed of HD if one parent has Huntington’s (Hh)
1) everyone with mutated gene will get HD
2) 50% chance of each offspring inheriting affected gene
3) inheritance is independent of gender
Prevalence of HD
Increasing
Higher prevalence in America, Europe, Australia etc
Faulty gene in HD
HTT
Poly glutamine tail (CAG) (length responsible for HD)
10-30 CAG repeats (poly glutamine repeats)
Normal HTT gene
36+ repeats of CAG (polyglutamine tail)
Diseases HTT gene
Poly-Q expansion and anticipation
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
Age of onset of HD
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)
Clinical progression
Prodomal - chorea biggest increase then cognitive, the motor
Manifest - motor impairments biggest then cognitive then chorea
2 phases of HD
Phase 1) neurones, signalling and connectivity affected
Phase 2) death of neurones (motor impairment seen)
Symptoms of HD
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
Symptoms: physical
Jerking/ Fidgety motor deficits
Clumsiness
Slurred speech
Abnormal eye movements
Swallowing issues
Weight loss
Involuntary movements
Incontinence
Symptoms: cognitive
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
Normal function of basal ganglia
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
Neuropathology of HD (basal ganglia)
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
Features of neurones selectively susceptible to degeneration in HD - direct pathway
Cortex, putamen, globus pallidus, thalamus, motor cortex, muscle/movement
Features of neurones selectively susceptible to degeneration in HD - indirect pathway (EXTRA READING)
Medium spiny neurone
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
Neuropathology progression (grades)
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
HD aggregates: enriched in N terminal fragments
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
Inclusion bodies
Insoluble protein aggregation
>40Qs
Loss of function (LOF)
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)
Gain of function (GOF)
Extra activating imparted by mutant protein (eg expanded plyQ creates protein comforters which are toxic; create new activity/interactions - albeit dysfunctional)
Pathological roles of mtHTT protein
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
MtHTT and transcriptional machinery
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
Loss of function example
Normal HTT removes REST allowing transcription of gene eg BDNF
MuHTT cannot remove REST
Gain of function example
inhibition of CREB dependent transcription (inhibition of CBP)
Can Mutant huntingtin regulate epigenetic changes
Yes
Can cause changes in DNA
Through inhibition deacetylases
GAIN OF FUNCTION
Mitochondrial dysfunction and HD
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
Anti-apiptotic (IAP) activity lost
Loss of function
Normal HTT blocks procaspase -9 by direct binding
Procaspase -9 not blocked my muHTT so increased sensitivity
Degeneration by dying back
Neurone degeneration starting from axonal projection
Why are medium spiny neurones more susceptible to degeneration
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
Huntington mediated dysfunction
Transport deficits
Transmitter release deficits
Ca2+ homeostatsis issues
Proteosomal dysfunction
Signalling dysfunction
(Autophagy - protein and membrane clearance)
Properties of neurones that are relatively susceptible
No common biochem characteristics among main neuronal pops effected by HD
Increased vulnerable if neurons with longer and more prominent axons
Treatments for HD
All targeted at alleviating symptoms
Chorea - tetrabenasine (FDA approved), ziprasidone
Depression - citalopram/fluoxetine
Anxiety - lozazepam
Muscle tremors - clonazepam
Cognitive dysfunction- donepezil
Therapeutic targets/strategies
Prevent muHTT regulating system deactylases so kinase inhibition and GM1
Autophagy enhancers and chaperone enhancers
KMO inhibition, immunomodulation
HTT loading (ASO or RNAi)
ASO (Antisense oligonucleotides)
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
