JPND GBA1 mutations in Parkinson disease: clinical and biochemical prodrome, risk profile and pathogenetic modelling for therapeutic intervention.

GBA1 mutation increases PD risk by 20-30x.

The UK group has established the largest published cohort of GBA1 mutation carriers 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.

Harmonised international longitudinal evaluation of GBA1 carriers in the established clinic based cohorts to determine prodromal clinical features , cognition, anxiety, depression), biochemical phenotype and identify those at high risk for conversion to PD. 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.

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 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.

Changes in the GBA gene are found in approximately 10% of patients with Parkinson disease (PD). This represents the most important risk factor for PD discovered to date. Each GBA mutation carrier has up to a 30x increased risk for developing PD during their life. Research to date shows that individuals with the GBA mutation begin to show early changes in certain features such as loss of smell, subtle movement problems etc. Together with certain alterations in blood and spinal fluid, these clinical findings can be used to identify the group most at risk of developing PD amongst GBA mutation carriers. In addition, even PD patients without mutations of this gene show alterations of the activity of the GBA enzyme in the brain. This means that some of the lessons we learn from GBA carriers may be applicable to PD patients in general. This overlap of GBA-related PD to PD in general is particularly important in terms of developing therapy that might be applicable to all PD. The applicants have developed large cohorts of GBA mutation carriers and propose to harmonize the study of these individuals across the countries. This will provide a very large group with which to study the evolution of PD from its earliest stages before diagnosis and to develop a biomarker profile to identify those at most risk of PD. The researchers are also actively pursuing the study of how GBA mutations cause PD and have already identified a new potential drug class (small molecule chaperones) that have shown promise in cell and animal models of GBA-related PD. The applicants will collaborate in the use of these models and also of samples taken from patients to further develop and test these agents towards their use in clinical trial.