Dr F Giorgini
University of Leicester
Targeting Parkin and Mitochondrial Dynamics in Huntington's disease
Huntington’s disease (HD) is an incurable, fatal neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein. This mutation causes HTT to misfold and aggregate, leading to widespread dysfunction and death of vulnerable neurons. As with several other neurodegenerative disorders, the pathogenesis of HD has been closely linked with mitochondrial dysfunction, which includes alterations in mitochondrial dynamics (e.g. increased mitochondrial fragmentation). In preliminary studies we have recently found that the Parkinson’s-linked protein parkin alleviates several disease phenotypes in HD flies when overexpressed. Parkin plays a role in clearance of damaged mitochondria (mitophagy), via modulation of mitochondrial dynamics. Here we propose to further investigate the mechanisms underlying parkin protection in HD fruit flies and a PC12 cell model, and also explore the role of mitochondrial dynamics and mitophagy in pathogenesis of this disorder. We will use genetic approaches to modulate parkin expression in HD models – as well as related proteins (e.g. PINK1, Mfn, Opa1, Drp1) – and ascertain the influence upon mitochondrial phenotypes (e.g. mitochondrial morphology, mitochondrial respiration). Relatedly, as parkin has been found to participate in protein degradation and autophagy of aggregated molecules and reduce proteotoxicity, we will also explore the relationship between parkin and HTT. In total, this work will explore the protective role of parkin in HD, and interrogate mitophagy and mitochondrial dynamics in this disorder. These studies may ultimately contribute to therapeutic strategies for HD.