Mapping the physiological regulation and function of the Parkinson's disease-associated kinase PINK1

Parkinson's disease is now the fastest growing degenerative brain disorder in the world. It is due to the loss of dopamine neurons in the brain but despite decades of research there are still no treatments that can cure or slow the course of the disease. As a clinical neurologist who sees patients with Parkinson’s, it has been my mission to understand the basic molecular mechanisms that might be driving the loss of neurons and to deliver new treatments for my patients. I previously made a major contribution to the discovery of mutations in the PINK1 gene in patients with familial Parkinson’s and have since established a world-leading laboratory recognised for ground breaking discoveries that we have made on the function of PINK1. PINK1 encodes an enzyme known as a protein kinase and we have found that this works very closely with another Parkinson’s-linked protein known as Parkin. Our work has found that when our cellular batteries known as mitochondria are damaged, PINK1 and Parkin act in concert to facilitate their removal in a process known as mitophagy. Our work indicates that when PINK1 or Parkin are faulty, as can happen when patients have gene mutations, there is a build-up of damaged mitochondria which exerts a stress on brain cells triggering their loss and the development of Parkinson’s symptoms. Our research findings have also been exploited by pharmaceutical and biotech companies to accelerate drug development for Parkinson’s patients. In 2024 Abbvie and Mission Therapeutics independently launched human Phase 1 clinical trials of brain penetrant molecules they have developed that boost PINK1 function and mitophagy as potential new drugs for Parkinson’s patients. Whilst these trials hold promise, much of our understanding of the function of PINK1 to date has largely been derived from artificial cell systems such as human cell line models and the role of PINK1 in the brain remains largely unknown. In this programme of research, I will bring together my unique expertise of clinical neurology and PINK1 biology with internationally leading collaborators to transform our understanding of how the PINK1 pathway is controlled and functions in the brain. Our research will be multi-disciplinary using state-of-the-art methods and technologies in molecular biology, protein sequencing (mass spectrometry), organelle biology, and neural biology in mice models in which PINK1 activity is altered. We aim to uncover the upstream control mechanisms that govern how PINK1 responds to mitochondrial stress in the brain using new mouse models that my lab has recently generated. We will also define in which cell types in the brain, PINK1 operates using mouse models that enable rapid isolation of organelles including lysosomes, the latter playing a vital role in removing damaged proteins and mitochondria. We will also follow up on exciting preliminary data we have generated to identify new components of the PINK1 pathway that may compensate for the loss of Parkin in the brain and which could represent potential drug targets for Parkinson’s. Finally, we will collaborate with experts in human brain pathology, genetics and human brain models to validate the importance of our discoveries in human Parkinson disease. Our proposed research has high potential to transform our understanding of the critical pathways controlled by the protein kinase PINK1 in the brain and may lead to new ideas for better treatment and diagnosis of Parkinson’s.