Huntingdon's Disease Flashcards
what is huntingdon’s disease?
An autosomal dominant , hereditary neurodgenerative disease
Does inheritance depend on gender?
no (independant of gender)
what three things is HD characterised by?
- cognitive
- behavioural
- motor dysfunction
when was HD recognised as a inherited disorder?
1872
where is there a higher prevalence of HD?
America, Australia and most european and western countries
where is there a lower prevalencec of HD?
Asia and Africa
Japan and China
which chromosome is HD located on?
4
what about the HTT gene causes the development of HD?
expansion of the gene
What is the job of the HTT gene?
to pull in its glutamine tail
how many repeats give rise to normal HTT function?
10 to 35 repeats
how many repeats are associated with onset of HD?
36 repeats or more
what is anticipation?
the earlier onset with each generation
what is the three stages of clinical progression
Presymptomatic
Prodromal
Manifest
What is stage 1 of clinical progression of HD?
Presymptomatic - you may carry an elevated number of copies but you haven’t manifested any symptoms
what is stage 2 of clinical progression of HD?
Prodromal - when you’re already manifesting some symptoms and you may be picked up by a clinician or not
what type of neuron does HD mainly affect?
Medium Spiny Neurons
makes up 95% of neurons
what is the two main things mtHTT leads to (neurodegen)?
- dysregulated transcription
- impairment of proteostatis
what three things can occur due to mtHTT’s effects?
- synaptic dysfunction
- mitochondrial toxicity and energy imbalance
- axonal transport impairment
what are the two misfolding pathways that mtHTT can lead to ?
- LOF : sequestering proteins into aggregates away from where it acts, modifying protein interaction making them weaker so binding is lost
- GOF : expanding PolyQ creates protein conformers which are toxic and create new activity/ interactions
how does mtHTT affect transcriptional machinery?
- inhibits 75% of transcription
- inhibits histone modifications, reducing transcription of genes (acetylation enzymes in particular)
- eg. inhibition of CREB dependant trancription
what can LOF look like in mtHTT?
Anti-apoptotic activity lost
- HTT blocks procaspase-9 by direct binding but mtHTT has reduced procaspase-9 binding
what can GOF look like in mtHTT?
- enhanced sensitivity of mPTP to Ca2+ - inducing pore opening and release of Cytc
- reduced membrane potential
- decreased Ca2+ buffering capacity
- Increased in ROS production
Name two HTT approved drugs?
Tetrabenazine
Deutetrabenazine
what are ASO (Antisense Oligonucleotides)?
Allele-selective drugs, that bind to and target for degradation, mtHTT mRNA via single nucleotide polymorphisms
what four factors cause variability in disease progression?
1) CAG repeat length
2) Genetic Modifiers
3) Enviromental Factors
4) Epigenetic factors
what is the mutation of HTT?
an abnormal expansion of a glutamine stretch (PolyQ) in its N-terminal sequence
describe axons in mtHTT?
- transporter deficits
- transmitter release deficits
- Ca2+ homeostasis
- Proteosomal dysfunction
- signalling dysfunction
describe Medium Spiny Neurons in HD?
- high level of glutamate cellular depolarisation (NMDA mediated Ca2+ influx)
- high firing rate and high metabolic demands
- long projection axon very dependant on efficient transport
- selective expression of neuropeptides and selective expression of Ca2+ binding proteins
