JPND GBA - personalised medicine for Parkinson disease: clinical and therapeutic stratification

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Parkinson disease (PD) has a lifetime risk of 3-4%, and there are approximately 60,000 new cases annually in the EU. All PD-related costs in the EU are estimated at 13 billion euros per annum. Recent advances in PD have identified that glucocerebrosidase 1 (GBA1) mutations are numerically the most important risk factor for PD. They are found in 10-15% of PD (25% in Ashkenazi Jews), and increase the risk for PD by 20-30x.PD involves the loss of brain cells (neurons) and the accumulation of a protein called alpha-synuclein (a-syn). GBA1 mutations cause impaired activity of the glucocerebrosidase enzyme (GCase) that is involved in the normal breakdown of unwanted or redundant cell constituents, including proteins. It has been shown that GBA1 mutations and reduced GCasae activity result in an increase in a-syn concentrations. Intriguingly, accumulation of a-syn causes impaired GCase activity in the normal enzyme. Thus there is a strong reciprocal relationship between GCase activity and a-syn levels. On this basis, it is considered that the GBA1 mutations that lead to GCase inhibition, initiate a self-amplifying cycle of GCase deficiency and a-syn accumulation that causes PD. This is reflected in those that carry GBA1 mutations and develop PD by their earlier onset and more rapid progression than those without GBA1 mutations.In this project we will investigate the evolution of clinical features prior to and during the development of PD in those that carry GBA1 mutations. The participants have access to cohorts of those with GBA1 mutations, with and without PD (>700 un the UK). We will integrate the web-based clinical assessments developed in the UK cohort with those in Italy and Spain to understand the pattern of prodromal features and how they evolve to clinical PD. We will also collect samples for biomarker analysis so that we can combine these with the clinical characteristics to identify those within the cohorts who are most at risk for the development of PD. Patients will be asked to provide skin scrapes so that we can culture these cells and convert them through an established protocol, into dopaminergic neurons - the type that degenerate first in PD. These stem cell derived models will be used to investigate specific aspects of the cellular biochemical effects of GBA1 mutations to understand the basis of the link with increased a-syn levels. as part of this we will develop an advnced model of the dopaminergic neurons in 3-dimensions, a so-called brain organoid. These models are valuable to understand the spatial spread of a-syn from one neuron to another. We hypothesise that GBA1 mutations will accelerate the spread of a-syn.Our stem-cell derived models, including the organoids will also be used to test whether a compound (ambroxol) is capable of reversing the effects of GBA1 mutations. Ambroxol is a molecule that binds to mutatant GCase and delivers it to its correct location within the cell (the lysosome). It is an a repurposed drug, currently on sale as a cough linctus. In cell, stem cell, fly and animal models, amroxol has been able to increase GCase activity in GBA1 mutation models, and reduce a-syn levels. Therefore it represents a promising compound for future investigation as a potential drug to slow PD.