Parkinson’s disease (PD) is characterised by the specific degeneration of midbrain dopaminergic neurons (mDANs) and presence of cytoplasmic inclusion bodies containing misfolded aggregated a-synuclein (a-syn) in the mDANs that remain. Familial PD is associated with mutations in a-syn, a presynaptic protein, which, upon subcellular fractionation, is localised to the mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a structurally and functionally distinct subdomain of the ER. The research group at Columbia University led by Serge Przedborski that were the first to identify the MAM localisation of wild-type a-syn also found that overexpression of the pathogenic point mutation p.A30P in human a-syn resulted in its reduced association with MAM. Furthermore, this was associated with reduced ER-mitochondrial apposition, a decrease in MAM function as evidenced by altered phospholipid synthesis, and an increase in mitochondrial fragmentation. In this proposed international collaboration, using the expertise of the Przedborski lab together with the unique a-syn patient-based cellular models and high-content high-throughput compound screening (HCS/HTS) expertise available at the Krueger lab at the LCSB. We will investigate the interaction of pathogenic a-syn from the p.A30P, p.A53T, duplication and triplication SNCA mutations using isogenic cell lines to distinguish the pathogenic effect of the a-syn mutation isolated from the patient genetic background. Therefore we use an enriched population of mDANs to determine cellular phenotypes for compound screenings that define disease-modifying compounds instigated by the effect of pathogenic a-syn have at the MAM. In an international collaboration that will allow the exchange of personnel, material and expertise from both groups, we will investigate MAM and mitochondrial phenotypes and propose to revert them by repurposing FDA-approved compound libraries available at the LCSB leading to the identification of MAM-specific treatment clinically approved candidate for the treatment of PD.