Huntington's Genetics and Biochemistry Flashcards
What is the genetic cause of Huntington’s disease?
a CAG trinucleotide repeat
causes an abnormally long Huntingtin protein
What is the inheritance pattern for HD?
autosomal dominant disorder - children of affected parents have 25%
Who sequenced the Hunginton gene? WHere?
Nancy Wexler in Lake Maracaibo Venezuela
True or false,
Like AD, HD stems form multiple genetic causes.
false - only ONE cause…in every single patient
What is the prevalence of HD? Who gets it most often?
1/10,000 or northern european background
much less prevalent in Asian and African populations
no gender variation
age of onset 35-50, but ranges from 2-85
What is the life expectancy after an HD diagnosis and what are the typical causes of death?
15-20 years
aspiration pneumonia, heart disease, falls, suicide, violence
Where in the brain is Htt expressed?
it’s widespread in peripheral tissues, and in th ebrain it’s expressed in neurons - essential for development, but we don’t really know it’s function yet
Where in the brain are neurons most affected by mutant Htt?
the striatum
How did they map the geme?
recombination frequency family linkage mapping
What does the CAG repeat encode for?
glutamine (Q)
(which is why it’s a polyQ tract)
What is the likely cause of the CAG repeat?
not fully known, but likely involves defects in DNA replication fidelity – initially in the germ line, but then in somatic cells as disease progresses
What is the normal number of polyQs? At what number do you start to see HD and at what number do you have 100% penetrance?
less than 35 is normal
36-41 has incomplete penetrance
40-60 polyQ repeats gives you 100% penetrance
over 60 gives you juvenile onset HD
What is anticipation and how does it relate to HD?
In genetics, anticipaiton is when the age of onset tends to decrease in successive generations
this is definitely the case in HD, where children almost always have onset of symptoms earlier than their parents - sometimes even BEFORE their parents present!
Is anticipaiton more likely when inheritance is from a maternal or paternal acarrier? Why?
paternal
they make sperm their whole lives, so there is a greater mutation risk in their germ line
Besides anticipation and # of CAG repeats, what can influence age of onset and severity of symptoms in HD?
Modifier genes (affects about 30-40% of the disease)
polymorphisms in GluR6, ApoE4 is protective while ApoE2/3 genotype decreases age of onset in males, variants in NMDA receptor, SNP in the PGC1-alpha gene
What environmental factors hav ebeen found to affect HD (and other neurodegenerative diseases)?
omega3 oils are protective while omega6 oils increases susceptibility
environmentla enrichment slows disease progression
How many neurodegenerative diseases have been ofund to be due to expanded polyQ tracts so far? Inheritance?
9
all autosomal dominant except Kennedy’s disease which is x-linked recessive
What is the pathogenesis for HD (and the other polyQ diseases)?
you get an abnormally lengthed protein which undergoes proteolytic cleavage
specifically from exon 1 of the Htt gene, you get an increased rate of cleavage at a nearby site, resulting in the release of a toxic fragment
while the wildtype fragment would noramlly get degraded in the cytoplasm, this one doesn’t
they enter the nucleus of neurons and accumulate as protein aggregates
What are the protien aggregates in the nucleus called?
nuclear inclusions
What do the nuclear inclusions do?
they form basket-like structures that trap other proteins, especially trasncription factors and wildtype Htt
Where in the brain do NI occur? Before or after clinical symptoms?
striatum and cortex
before clinical symptoms
What is the controversy around the NI?
some studies suggest they’re actually neuroprotective and may protect against cell death - that smaller soluble aggregates are the source fo the dysfunction
What are the 6 major cellular defects associated with HD?
- dysregulation of transcription
- altered neurotransmitters
- excitotoxicity
- interference with wildtype Htt - changes in axonal transport and synaptic fucntion
- apoptosis
- oxidative stress from mitochodnrail dysfunction
Why does haploinsufficiency NOT explain the HD phenotype?
humans that are heterozygous at the Htt develop no pathology
mice that express an expanded CAG repeat fragment in addition to two wildtype copies of Htt do develop HD
What symptoms come first in HD?
the psychiatric symptoms of depression, irritability, impulsiveness and aggression
may precede motor onset and cell death by as much as 20 years!
What is a major target for the dysregulation of transcription in HD and what is the effect?
CBP - a histone acetyltransferase
this means you don’t get acetylation of the DNA, so it doesn’t open up for transcription and you don’t get transcription of necessary genes like the D2 receptor gene
(you also get trapping of transcription factors in the baskets)
What NT is deficiency in HD?
GABA - because of a loss of spiny neurons in the basal ganglia
Upregulation of what receptors in HD causes excitotoxicity associated with chronic exposure to excitatory AA like glutamine and glutamate?
NMDA receptors
What are basically the 5 points along the corticostriatal pathway where dysfunction may contribute to excitotoxicity?
- increased glutamate release
- reduced uptake of glutamate by glia
- hypersensitivity of the NMDA receptors
- altered intracellular ca2+ homeostasis
- mitochondrial dysfunction
How does mitochondrial dysfunction lead to cell death>
you get release of cytochrome C leading to caspase activation and cell death
What is a target of Htt that is a key regulator of mitochodnrail biogenesis and respiration?
PGC-1alpha
