Investigating PINK1/Parkin Function and Dysfunction in Drosophila: Insights into Mitophagy, Calcium and Gut-Brain Axis

Host: Miratul Muqit & Amos Liang

Venue: Sir Kenneth & Lady Noreen Murray Seminar Room, CTIR 2.84

Abstract:

Parkinson’s disease (PD) is a common neurodegenerative movement disorder that is typically caused by a combination of genetic and environmental factors. Relatively rare inherited forms of PD have delivered incredible insights into the pathogenic mechanism and have consistently highlighted defects in proteostasis and mitochondrial dysfunction. Two genes linked to inherited PD, PINK1 and PRKN, provide the strongest links to mitochondrial dysfunction as their encoded proteins (the kinase PINK1 and ubiquitin ligase Parkin) function to signal the selective degradation of mitochondria – a process termed mitophagy. Many aspects of PINK1/Parkin function are deeply conserved through evolution. Since their development, the Drosophila models of the orthologous genes, Pink1 and parkin, have delivered fundamental insights into their physiological function. The strength of the model is due largely to the robust phenotypes of the genetic knockouts which confer mitochondrial disruption, locomotor deficits and neurodegeneration under basal conditions. Applying the powerful genetic tools available in Drosophila has uncovered important molecular and cellular aspects of Pink1/parkin disruption to tissue and organismal health. A key advantage of analysing Pink1/parkin function in an animal model is the ability to interrogate inter-organ, such as the gut-brain axis, as well as systemic impacts on neurodegeneration and healthspan. Here I will present our latest advances on understanding the physiological roles of Pink1/parkin as well as the consequences of their dysfunction and therapeutic opportunities.

Bio:

Dr Alex Whitworth is an MRC Investigator in the MRC Mitochondrial Biology Unit at the University of Cambridge. His research team is focused on understanding the underlying mechanisms of neurodegeneration and identifying potential therapeutic targets, primarily using Drosophila as a powerful in vivo model system. Following a PhD at the University of Cambridge, studying developmental genetics in Drosophila, he joined the laboratory of Prof. Leo Pallanck at the University of Washington, where he developed several new fly models of Parkinson's disease, including PINK1 and Parkin. In 2005, he started his own research group at the University of Sheffield and was recruited to Cambridge in 2015. Dr Whitworth’s group has made fundamental discoveries into the mechanism of action of the PINK1-Parkin pathway that impacts on the long-term health of the mitochondrial network and ultimately on neuronal survival. The team has also recently identified mitochondrial calcium as an important factor in PINK1/Parkin related neurodegeneration and are investigating the intersection with the gut-brain axis. Discoveries from these investigations will help identify potential therapeutic targets to boost mitochondrial health to maintain neuronal survival.