To identify biological subtypes of Parkinson’s by combining genetics and environmental exposures, as well as biological signatures with the PD Risk Factor Questionnaire, adding the UK Biobank COVID-19 and viral infection questions, to underpin the development of biomarkers and strategies for precision medicine. This project will be split into five specialist focus areas:
Mitochondrial dysfunction
Mitochondrial damage is a feature of both hereditary and idiopathic Parkinson’s. Mitochondrial DNA can be detected in blood samples where mitochondrial recycling and repair processes are dysfunctional, for example, in people with mutations in genes PINK1 or PRKN.
Ubiquitin systems
The ubiquitylome represents the targets modified by the addition of the small protein ubiquitin which regulates protein activity, function and degradation. Ubiquitin signalling is known to be defective in Parkinson’s, yet is largely unexplored as a source of clues to unravel Parkinson’s mechanisms as well as biomarkers to aid in disease progression monitoring.
Lysosomal dysfunction
Lysosomal degradation is a cellular “garbage disposal” system. Proteins and cell components that are damaged or unwanted are flagged and sent to the lysosome—an organelle filled with acidic enzymes—to be broken down and recycled. Defects in this process can lead to the development of Parkinson’s.
Inflammatory signalling
Inflammatory signalling has long been associated with neurodegeneration and Parkinson’s disease, with recent data supporting chronic inflammatory signalling as a driver of Parkinson’s and not just a consequence. The triggers for neuroinflammation in Parkinson’s remain unclear, but mitochondrial damage has been implicated.
Oxidative stress and neuronal death
The mechanism(s) which lead to the death of dopaminergic neurons is not yet fully understood. We need to identify how and why neurons die if we hope to block it to stop neurodegenerative process. Oxidative stress is thought to play a key role in neuron death. Using Parkinson’s patient-derived cells we will identify the different triggers for neuron death and develop new drugs that target these triggers. neurons.
