Signalopathies - Huntington's Disease Flashcards
What is HD?
= originally Huntington’s Chorea
= one of most common genetic disorders
(5-10 case per 100,000 people worldwide)
= autosomal dominant neurodegenerative disease
= irregular movements (chorea), cognitive and psychiatric disorders
= fatal within 15-25 years of diagnosis
= neuronal loss (seen in loss of grey matter volume)
= results in increase in astrocytes (astrocytosis) due to neuronal loss
What is Huntingtin?
= ubiquitously expressed protein (350 kDa) encoded by the Htt gene
= expressed in neuronal cells
= has many functions
(including post-synaptic density (PSD) signalling in synapses)
How does PSD signalling normally work?
Htt interacts
= strongly with the NMDAR complex
= weakly with IP3R
Glutamate activates
= NMDAR glutamate receptor
(= extracellular Ca2+ influx)
= mGluR5
(= increased IP3)
Small IP3-induced Ca2+ conc increase
= due to low sensitivity of IP3R to IP3
= generation of non-pathogenic Ca2+ signals
What happens to PSD signalling in HD?
Mutation causes polyglutamine expansion in the N terminus of Huntingtin (Httexp)
Polyglutamine expansion of Htt
= increases DHPG (glutamate receptor agonist)-induced Ca2+ conc elevation
Httexp
= enhances NMDAR increased Ca2+ influx
= sensitises IP3R to IP3 = increased Ca2+ release
= low Ca2+ conc in ER = increased Ca2+ release via SOCs
= increased Ca2+ influx via vGCC
= loss of Ca2+ binding proteins
Supranormal Ca2+ conc
= triggers downstream pathogenic Ca2+ dependent pathways and neuronal loss
What are some genetic therapies for HD?
Antisense oligonucleotides
= DNA/RNA that modify protein production by binding to RNA made by faulty genes
BUT clinical trials halted due to issues in
= reaching correct part of brain
= suppressing healthy Htt as well as mutant version
Alternative
= use of Adeno-associated viruses for delivery
(rather than spinal injections)
= ongoing clinical trial
