The role of organelle contact sites in Parkinson’s disease-associated α-synuclein toxicity: insights from a yeast model

This PhD project aimed to identify novel players involved in α-syn toxicity, with a particular focus on those involved in inter-organelle communication. The general goal was to elucidate the molecular mechanisms that underlie α-syn toxicity and uncover the role of MCSs in this process. The first experimental part of this study was dedicated to identifying MCS deletion mutants involved in mediating α-syn toxicity. In order to achieve this, we conducted a targeted, systematic screening by expressing α-syn and its mutants in multiple deletion strains that lacked contact site tethers and evaluated the resistance of these strains to α-syn toxicity. The second experimental part of this project aimed to investigate the mechanistic basis of the previously observed resistance to α-syn toxicity in the identified MCS deletion mutants, with a focus on the Vps39 tether. This initially involved the identification of the TORC1 downstream effector Sch9 as a Vps39-vCLAMP regulator. Subsequently, via mitochondrial and vacuolar pH analysis combined with lipid profiles, we explored the role of Vps39 by identifying alterations that could contribute to α-syn toxicity. Our findings highlight the involvement of α-syn expression in these pathways and emphasize the significance of Vps39 in mediating α-syn-induced toxicity. Overall, this project sheds light on the role of MCS in regulating α-syn toxicity and proposes potential targets and mechanisms for further research.