Identification of genetic modifiers of Parkinson's disease in yeast

• Main Author: Pui, Carmen Sze Min
• Other Authors: Choe Young Jun
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/166445
• Institution: Nanyang Technological University

Alpha-synuclein (αSyn) is a primary constituent of Lewy bodies (LB), the hallmark pathological structures present in the brains of individuals affected by Parkinson's disease (PD). Despite the conventional understanding of fibrillar αSyn protein-protein aggregation in inclusion bodies, a growing body of evidence suggests that these structures represent clusters of cytoplasmic vesicles, with αSyn localized to the periphery of the vesicles. To understand more about the underlying mechanisms, yeast was utilized as a model to investigate various vesicular trafficking-related genes. Results showed all null mutants displayed an increase in αSyn aggregation, indicating a causative link between membrane trafficking dysfunction and αSyn aggregation. Additionally, disrupting mitochondrial fusion and fission activity increases αSyn aggregation. The toxicity of αSyn aggregates differs between each mutant strain. Interestingly, I demonstrated that the diminished lipid binding affinity of αSyn mutants is still able to form cytoplasmic foci in some mutant strains which could be a different model of aggregation. Therefore, different perturbations to the membrane trafficking pathway could result in a different composition of lipid-lipid clustering that could potentially affect αSyn toxicity. Understanding this clustering dynamic provides a deeper insight into PD pathogenesis, and may provide opportunities to develop effective therapies for this debilitating disease.