Huntingtons Disease Flashcards
Define Huntingtons
progressive neuropyschiatric disorder caused by an autosomal dominant mutation on chromosome 4 charcaterized by motor cognitive and pyschiatric symptoms
What does the mutation in huntingtons do?
CAG nucleotide repeat expansion which encodes for a variably elongate polyglutamine chain to be present in the huntington HTT protein
Diagnosis?
Genetic testing
When was the huntingtons gene discovered
1993 by mcdonald et al
Describe the genetics of huntingtons?
chromosome 4 mutation autosomal dominant 100% penetrance usually 21 CAG repeats when the exon 1 of HTT gene > 36 repeats causes polyglutamine tracts
What did Brinkaman 1997 say?
greater length = more severe = anticipation
What is the function of Htt gene?
function unknown but interacts with many proteins an conserve across species such as drosophilia, mice, sea slug aplysia
Sah et al- rehulates apoptosis
Harges and wanker 2003- knockout mice did not survive embryonic development
Talk about mHtt aggregates
Glutamate = polar
Abunance causes links between proteins –> “sticky” molecules with H+ bonds
accumulation is toxic causing clathrin endocytosis dysfunction, mitochondrial toxicity an vesicular transport dysfunction
Choi et al 2014
Believe that wild type HTT is involved in long term memory as shown by experiments in aplysia where HTT was shown to be essential in pre and post synaptic for LTP
Talk about aggregates being neurotoxic and who says this?
cytoplasmic proteins are usually degraded by lysosomes
misfolded proteins- ubiquinated and degraded by proteosomes
dysregulation of this UPScauses cell death- bence 2011
what else does the mHtt aggregaates bind to?
sticky molecules that bind to other glutamate rich proteins including P53 and CREB binding protein
Describe evidence that the aggregates are neuroprotective
greenburg 1998 found that fragment size an folding didnt correlate with the rate of death so maybe aggregation is a beneficial mechanism to inactivate the toxic forms of huntington with expanded polyglutamine
how does tetrabenazine work?
basically blocks the VMAT which chucks dopamine into vessicles and also blocks the dopamine receptors so that there is LESS DOPAMINE because the damn dopamine acts on basal ganglia to INCREASE movement
Talk about gene silencing
ASO- anti-sense oligonucleotides is a form of treating genetic disorders where the ASO will bind to the complimentary mRNA and cause reduced traslation of HTT by trigerring RNase-mediated degradation
Talk about another form of gene silencing apart from ASO
RNAi approach- enogenous RNAi process where small inteferring RNAs(siRNA) bind to mRNA and cause formation of RISC that prevents the translation of HTT by cleaving the mRNA
