Identification of genetic modifiers of Parkinson’s disease in yeast

Alpha-synuclein (α-Syn) is a critical pathogenic player of Parkinson's disease (PD), which accumulates in the form of Lewy Bodies (LBs). It was previously reported that LBs resulted from protein-rich amyloidogenic fibrils. However, multiple studies in recent years report that they are instead a...

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Bibliographic Details
Main Author: Yap, Ernest Gim Seng
Other Authors: Choe Young Jun
Format: Final Year Project
Language:English
Published: Nanyang Technological University 2023
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Online Access:https://hdl.handle.net/10356/172188
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Institution: Nanyang Technological University
Language: English
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Summary:Alpha-synuclein (α-Syn) is a critical pathogenic player of Parkinson's disease (PD), which accumulates in the form of Lewy Bodies (LBs). It was previously reported that LBs resulted from protein-rich amyloidogenic fibrils. However, multiple studies in recent years report that they are instead a mix of vesicular clusters with α-Syn serving as a membrane tether. Moreover, the exact mechanism of α-Syn aggregation in PD pathogenesis has not been elucidated. Using a yeast model, I discovered that amino acid biosynthesis pathways are significant in α-Syn ability to form aggregates. In this project, I showed that yeast mutants defective for amino acid metabolism exhibited severe aggregation of α-Syn and suppressed growth under α-Syn-induced toxicity. The composition of the α-Syn clusters in these mutants was further investigated to reveal the preferential binding of lipid membrane class in the perivacuolar compartment (PVC) and t-SNARE endosomes. In addition, the puncta formation of yeast chaperone Sis1 was observed in the cytosol of the examined mutants expressing α-Syn. However, the chaperone did not colocalize with α-Syn clusters. In summary, amino acid biosynthesis pathways could be implicated in modulating the pathogenic behaviour of α-Syn, offering additional insight into the pathogenesis of PD.