Huntington's Disease
Huntington’s disease (HD) is a devastating neurodegenerative disorder that affects approximately 1 in 10,000 people. It is a late onset hereditable disorder characterised by neuronal dysfunction and cell death, primarily in the cerebral cortex and striatum, followed by progressive chorea, dementia, emotional dysfunction, and ultimately, death.
HD is caused by an expansion of a CAG repeat in the first exon of the HD gene resulting in an abnormally elongated polyglutamine tract in the huntingtin protein (htt). Although discovery of the HD gene in 1993 was a landmark discovery, the function of both wild type htt and the mechanisms by which mutant htt evokes cell toxicity have remained elusive. The genetic dominance of the disease and the demonstration that the expanded CAG per se is sufficient to evoke toxicity, both indicate that the mutant protein acts via a gain-of-function toxicity that kills striatal neurons. However, the causal sequence from mutant HD through to neuronal dysfunction and behavioural and cognitive impairment and death remains unclear.
Along with other neuropsychiatric and neurodegenerative disorders, HD progression is marked by long-term transcriptional and epigenetic changes. Our work focuses on identifying these transcriptional ad epigenetic dysfunction using cellular and animal models of HD and novel tools to attempt to rescue the dysfunction.
Our aspiration is that knowledge of these basic disease mechanisms will lead to identification of druggable targets that may delay or ameliorate HD symptomology.
Staff working on this disease are:
Noel Buckley
Angela Bithell