What The aim of this project is to understand how mutations in the gene GBA1, the most important risk factor for Parkinson Disease, lead to the emergence of the disease pathology. Mutations in GBA1, the gene encoding the protein Glucocerebrosidase, leads to decrease in the enzyme activity, the accumulation of lipid substrates as well as the deposition of toxic alpha-synuclein, the main constituent of Lewy Bodies found in the brain of patients with Parkinson Disease. One of the main outcomes of this research is to provide the currently missing basic mechanistic understanding of the relationship between GBA1 mutations, changes in Glucocerebrosidase activity, changes in lipid metabolism and the emergence of alpha-synuclein toxicity. Why Parkinson Disease is the second most common neurodegenerative disorder at older ages, causing disability and care dependency. To date, no effective diagnostic tools and treatments are available mainly because of our lack in understanding of the disease mechanisms. This research project aims at contributing basic mechanistic knowledge in order to provide a better understanding of the molecular determinants responsible for the early events of the disease. How We will combine biological and biophysical approaches to investigate how mutations in GBA1 can lead to alpha-synuclein aggregation in the test tube, in cells and in vivo. In particular, we will study the lipid composition of different membranes and protein deposits isolated from patients’ neuronal cells to identify specific changes in lipid properties associated with GBA1 mutations. Then, we will use experimental and theoretical biophysical methods to investigate whether GBA1 mutations are responsible for the initiation of alpha-synuclein aggregation, indirectly, through changes in lipid levels/properties and/or, directly, via interactions between Glucocerebrosidase and alpha-synuclein. SSR Parkinson Disease is the second most common neurodegenerative disorder at older ages, causing disability and care dependency. Over the next 40 years, the number of individuals affected by this incurable disease is expected to grow by 92% in Europe and this increase in the number of patients leads to a substantial social and economical burden on our societies. This project aims at providing the currently missing mechanistic understanding of the disease early events required for the development of more efficient diagnostic tools and pharmaceuticals.