Regulation and function of PINK1 kinase in Parkinson's disease (360G-Wellcome-210753_Z_18_Z)

£2,088,664

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) cause familial Parkinson's disease. My laboratory has contributed mechanistic understanding into how PINK1 functions in a common signalling pathway with the ubiquitin E3 ligase Parkin to regulate mitochondrial quality control. Highlights of our past work include the unexpected discovery that PINK1 can phosphorylate ubiquitin and the recent crystal structure of insect PINK1. To date it remains unknown whether our current understanding of PINK1 biology is conserved in neuronal cell types and tissues of physiological relevance to Parkinson's. To address this, we will employ quantitative proteomics to uncover novel substrates of Parkin in primary mouse neuronal systems as well as tissues of a Parkin Ser65Ala knock-in mouse model, we have characterised, that exhibits mitochondrial dysfunction in vivo. We will investigate how mutations in other Parkinson's genes particularly VPS35 regulate PINK1 signalling. We will investigate the mechanism by which human PINK1 becomes activated including solving the crystal structure of full length human PINK1 bound to its substrate ubiquitin. These analyses will provide a framework of knowledge that will be critical for the development and evaluation of PINK1 activators that are currently being explored as a potential therapy against Parkinson's.

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Grant Details

Amount Awarded 2088664
Applicant Surname Muqit
Approval Committee Science Interview Panel
Award Date 2018-04-10T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Senior Research Fellowship Clinical Renewal
Internal ID 210753/Z/18/Z
Lead Applicant Prof Miratul Muqit
Partnership Value 2088664
Planned Dates: End Date 2023-12-31T00:00:00+00:00
Planned Dates: Start Date 2018-07-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland
Sponsor(s) Prof Dario Alessi