Chamberlain Lab

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Huntington’s Disease (HD) is a neurodegenerative disorder caused by expansion of a CAG (encoding the amino acid glutamine) repeat region in the Huntingtin gene. The resulting protein, which has an expanded polyglutamine tract, exhibits an increased tendency to aggregate and form cytoplasmic and nuclear inclusions. S-acylation of huntingtin was shown to modulate its intracellular trafficking, and blocking this modification increases aggregate formation and neuronal toxicity. The finding that polyglutamine tract expansion reduces the interaction of huntingtin with the S-acyltransferase enzymes zDHHC17 and zDHHC13 (also known as HIP14 and HIP14L respectively) suggested that a loss of huntingtin S-acylation might be linked to pathogenesis in HD.

Interestingly, recent work has suggested that huntingtin is more than simply an S-acylation substrate of zDHHC17 and zDHHC13. Indeed, the S-acyltransferase activity of zDHHC17 is positively modulated by huntingtin, and this mode of regulation is lost when the polyglutamine tract is expanded to include a pathogenic number of repeats. The implication from this finding is that some features of HD may therefore reflect a loss of zDHHC17 enzyme activity. Supporting this idea, zDHHC17 knock-out mice were reported to display similar deficits to those seen in HD and mouse models of HD, including decreased striatal volume, loss of striatal medium spiny neurons, a decreased number of excitatory synapses, motor co-ordination changes and deficits in pre-pulse inhibition.

Our group is working to identify underlying mechanisms that might link zDHHC17 dysfunction with HD, with the long-term aim of rational design of novel small molecule modulators of zDHHC17 for the treatment of HD.

Past/Present Sponsors

MRC 

 Wellcome Trust

Diabetes UK

BBSRC

SULSA  

Palmitoylation

Palmitoylation is the most prominent type of S-acylation and involves the covalent and reversible attachment of a 16 carbon saturated fatty acid (palmitic acid) to cysteines of target proteins.