Investigating the mechanisms of Parkin-mediated mitophagy (360G-Wellcome-205909_Z_17_Z)

£99,277

Determining how cells maintain homeostasis under times of stress is vital to understanding a wide-range of disorders, from neurodegenerative diseases to cardiomyopathies. Autophagy is a catabolic cytosolic pathway that functions to degrade damaged organelles and mis-folded proteins, while providing a protective mechanism under stress. Mitophagy, the selective autophagic pathway for mitochondria limits oxidative stress by degrading damaged mitochondria through a mechanism involving ubiquitylation and recruitment of autophagic machinery. One mechanism of mitophagy, which is dysregulated during Parkinson’s disease, is the PINK1-parkin pathway. In this proposal, we will identify and characterise regulators of parkin which facilitate its recruitment to mitochondria. We will focus on an adaptor protein complex Tollip-Tom1, which has been suggested to be linked to this process, and which functions to regulate trafficking along both the endolysosomal and autophagic pathways. We will utilise microscopic imaging and biochemical assays to dissect the spatiotemporal regulation of parkin-mediated mitophagy following targeted loss of function of Tom1 and Tollip. In addition, we will utilise CRISPR-Cas9 technology, coupled to cDNA reconstitution experiments, and primary patient-derived fibroblasts to understand mechanisms of parkin recruitment following mitochondrial damage. The outcomes will provide crucial mechanisms of how cells regulate PINK1-parkin mediated mitophagy in order to maintain their health.

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Grant Details

Amount Awarded 99277
Applicant Surname Tumbarello
Approval Committee Science Seeds Advisory Panel
Award Date 2016-11-29T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Seed Award in Science
Internal ID 205909/Z/17/Z
Lead Applicant Dr David Tumbarello
Partnership Value 99277
Planned Dates: End Date 2019-11-02T00:00:00+00:00
Planned Dates: Start Date 2017-05-02T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East