Grant: Operating Grant: Joint Programme on Neurodegenerative Disease Research (JPND)

Mutations of the glucocerebrosidase gene (GBA1) are the most important risk factor for Parkinson's disease (PD). In Europe, at least 5-10% of all PD patients carry GBA1 mutations. A GBA1 mutation increases PD risk by 20-30x. GBA1-related PD has characteristics that are indistinguishable from the rest of PD cases, except that age of onset is slightly younger, cognitive deficit more common and progression more rapid. The UK team has established the largest published group of GBA1 mutation carriers and developed a protocol for their clinical and biochemical characterization to identify the starting/triggering features of PD in this high-risk group. This application will build on the existing links between the applicants to increase and integrate the UK patients' group with existing patients' groups of GBA1 mutation carriers in Italy and Canada. Equally, GBA1 mutant mice alone or in combination with alpha-synuclein excess (SNCA, another gene linked to PD) as double mutant mice, are available within the consortium. These mice, together with other in vivo models of PD, will be used to build on existing collaborative projects to investigate how these mutations •interact with known PD risk factors (aging and toxic exposures), •affect PD-like pathology in the form of alpha-synuclein aggregation and spreading, •modulate mitochondrial function (mitophagy, transport), protein degradation and redox homeostasis.