Mechanisms of ubiquitin signalling in Parkinson's Disease (360G-Wellcome-209347_Z_17_Z)

Neurodegenerative disorders, including Parkinson's Disease and dementia with Lewy bodies, are devastating diseases, with no known cure. They share a common histopathological feature, in that the deposits of insoluble aggregates found in the brains of patients are heavily modified by ubiquitin. Several genes that are associated with neurodegenerative disorders encode E3 ubiquitin ligases. One such ligase, Parkin, is mutated in > 50% of autosomal recessive juvenile parksinsonism (ARJP) cases. Furthermore, Parkin is found in the inclusions deposited in the brains of sporadic Parkinsonism patients. Parkin signalling is complex and heavily regulated, and our understanding of how it targets substrates is not well understood. This proposal aims to define the complete catalytic cycle of Parkin function, how proteins are targeted, how ubiquitin is relayed through the catalytic intermediates to target conjugation. This will require a combination of structural biology and chemical biology to capture individual states, and biochemistry to identify molecular determinants of Parkin activity. Understanding these catalytic processes at the molecular level, will not only impact on our understanding of the regulatory events taking place in vulnerable neurons, but will also provide the atomic detail needed to develop pharmacological compounds capable of restoring or disrupting enzyme function.