|
Project Topic
|
Mutations of the glucocerebrosidase gene (GBA1) are the most important risk factor for Parkinson 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 is clinically, radiologically, pharmacologically and pathologically indistinguishable from idiopathic PD, except that age of onset is slightly younger, cognitive deficit more common and progression more rapid. A primary goal of this project is the standardization of clinical and experimental practices for studying GBA1-linked PD, as a critical step toward the definition of diagnostic biomarkers, pathogenetic pathways and therapeutic strategies. The UK group has established the largest published cohort of GBA1 mutation carriers (>250) with 100 followed longitudinally and has developed a protocol for their clinical and biochemical phenotyping to identify the prodromal features of PD in this genetically stratified high risk group. This application will build on the existing strong links between the applicants to increase and integrate this UK cohort with existing cohorts of GBA1 mutation carriers in Italy and Canada. Members of the respective country’s GBA1 cohort will be studied by an identical protocol, based on that already published by the UK group, and followed up longitudinally. Results will form the basis of the clinical and biochemical phenotyping of prodromal and established GBA-PD in a large (>550) international cohort. This effort will be supported by a novel, but validated web-based system to expand initially the cohort in the UK and subsequently in additional centres. This web-based system (based on PREDICT-PD but modified for the GBA1 cohort) will seek to recruit an additional 800 GBA1 mutation positive individuals. This will be achieved through the index Gaucher disease cases that attend the two national Centres at the host institution in London and in Cambridge. The established and web-based cohorts will be used to provide a: Harmonised international longitudinal evaluation of GBA1 carriers in the established clinic based cohorts to determine prodromal clinical features (olfaction, motor function, bradykinesia, sleep disorder (RBD), cognition, anxiety, depression), biochemical phenotype (blood, urine, CSF) and identify those at high risk for conversion to PD. Assessment of the web-based group for signs and symptoms including anxiety (HADS), depression (BDI), bradykinesia (peg board), cognitive decline (MoCA, Wesnes), reduced sense of smell (UPSIT), abnormal sleep behaviours (RBD-Q) associated with the very early stages of PD. Participants will be required to undertake a questionnaire and a number of interactive assessments that includes the above, and which are designed to identify risk factors and early clinical signs of PD. Resource for cell models (fibroblasts, lymphoblasts, inducible pluripotent stem cells and adipose-derived neural crest stem cells). Genetically stratified group of individuals suitable for future clinical trials of agents targeted for those with GBA1 mutations with PD or at risk of PD. A portfolio of heterozygous GBA1 mutant mice (N370S, L444P) alone or in combination with alphasynuclein (SNCA) over-expression as double mutants, is available within the consortium. Other in vivo models will be generated, including innovative reporter mice that would allow non-invasive imaging of lysosomal biogenesis and function. These models, will be used to build on existing collaborative projects fulfilling the secondary goal of this project to investigate how GBA1 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 contribute to the pathogenesis of PD and how the effects of GBA1 mutations could be counteracted by administration of small molecule chaperones.
|
