L4 Huntington's Disease Flashcards
Who first described Huntington’s disease and when?
George Huntington in 1972.
What is Huntington’s Disease?
HD is an inherited disorder arising from an autosomal dominant mutation in the gene Huntingtin (HTT). The mutation is caused by excessive CAG repeats which result in an unstable protein with an abnormally long polyglutamine tract at the N-terminus.
What is observed in embryonic mouse-KOs of the HTT gene?
This results in a lethal phenotype. This means that the protein is critical for embyronic development.
What does a reduction in WT HTT cause in transgenic mice?
Motor, behavioural and structural problems.
What are six suggested roles for the HTT gene?
1) Vesicular trafficking.
2) Endocytosis mediation.
3) Vesicular recycling.
4) Cell division coordination.
5) Regulation of transcription and metabolism.
6) Apoptosis suppression and synaptic transmission.
What do gain of function mutations in HTT cause?
These mutations result in ubiquitous expression of mutant HTT protein.
This is thought to be the predominant toxic agent in HD.
What is the logical treatment for HD and why might this not work?
The therapeautic target of HTT should, in theory, reduce pathogenesis.
However, it has been shown that mutant HTT can also have a diminished function. As HTT is such an important protein, therapeutic targeting may result in worsening HD symptoms.
How is diagnosis of HD achieved?
By a physical examination and a genetic test for the expanded copies of CAG repeats in the HTT gene.
Medical imaging can also be used to confirm brain alterations associated with the disease e.g. CT/MRI can show early atrophy of the caudate nucleus.
What is the key correlation in HD?
The correlation is between the age of onset and the number of repeats in the HTT gene. The longer the repeats, the earlier the age of onset.
What are the 5 main symptoms of HD?
1) Chorea = random involuntary movement.
2) Tics = these are often rapid and focal.
3) Dystonia = repetitive muscle contractions. They are often associated with abnormal posture.
4) Myoclonus = brief, involuntary twitching of a muscle. These are very fast movements.
5)
What is the advantage of targeting mRNA as a treatment?
The mRNA is easily accessible in the nucleus or the cytosol and is unprotected by repair machinery. A reduction in HTT mRNA translation should be easier than modulating transcription or altering the gene itself.
What are the three main methods to reduce HTT mRNA?
1) Antisense oligonucleotides (ASOs).
2) RNAi compounds.
3) Small molecule splicing modulators.
What are ASOs and RNAi compounds?
These are nucleotide-based therapeutic molecules that selectively bind to mRNA and trigger RNA degradation machinery to dispose of the transcript.
What are DNA-targeting therapeutic agents expected to do?
Ameliorate all aspects of HD, including those mediated by alternative splicing.
What is CRISPR-Cas9 and how can it be used in DNA-targeting?
CRISPR and Cas form the basis of a prokaryotic immune system that recognises and destroys foreign DNA.
The Cas9 nuclease can be combined to produce a construct that is able to cut DNA with high precision at any chosen site.
CRISPR has the potential to excise CAG repeats and inactivate the mutant allele by inserting stop codons/missense mutations.
