Molecular basis for inherited Parkinson’s disease – mechanism of PINK1

Molecular basis for inherited Parkinson’s disease – mechanism of PINK1

Project details

Mutations in the protein kinase PINK1 lead to inherited forms of Parkinson’s disease. PINK1 is a key mediator of mitophagy, a specialized form of autophagy of damaged mitochondria. Work by previous students in my lab has revealed how PINK1-mediated phosphorylation of ubiquitin, and of the E3 ubiquitin ligase Parkin, activates mitophagy (see Wauer, Nature 2015 534(7565):374; Schubert Nature 2017,552(7683):51; Gladkova Nature 2018,xxx). Activators of PINK1 could boost mitophagy, and be useful to treat Parkinsonism (Hertz Cell 2013 154(4):737).

The aim of your project will be to understand structure and regulation of mammalian PINK1. For this, you will use a variety of biochemical, biophysical and structural biology methods, and also integrate in larger lab-wide efforts to understand physiology of PINK1/Parkin, and exploit its promise for drug discovery.

Protein structure
Structure of the PINK1 ubiquitin complex: how defects in ubiquitin phosphorylation lead to early-onset Parkinsonism

 

About our research group

My lab moves to the Institute in November 2018 from the MRC Laboratory of Molecular Biology in Cambridge, UK. We will form the core of a new division that focusses on understanding ubiquitin and ubiquitin-like modifications, and as such integrate with the many labs and divisions at the Institute, to uncover new links and discover new pathways regulated by ubiquitination.

A particular interest will be on neurodegenerative diseases, including Parkinson’s disease, for which exciting links to inflammation, a core strength of the Institute, are currently emerging. Eventually, we hope to turn our mechanistic insights into first medicines, that delay or stop the onset of neurodegeneration in humans.  

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