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  • 1. Gillespie, Breonna Characterization of the roles of mitochondria in the toxicity of α-synuclein in a respiratory cell model

    Master of Science (MS), Wright State University, 2023, Biological Sciences

    Although α-synuclein (α-syn) has been linked genetically and pathologically to Parkinson's disease, the mechanism by which it drives disease pathogenesis is not fully understood. When α-syn is overexpressed in yeast, it forms abnormal cytoplasmic accumulations and leads to cell death, resembling the phenotypes observed in neurons. Such yeast models have been widely used to uncover molecular mechanisms of α-syn toxicity, but the induction of α-syn relies on growing yeast in galactose, a fermentable carbon source. Yeast does not require cellular respiration when grown in galactose, thus limiting the understanding of α-syn toxicity when cellular respiration is essential for neurons. We developed a new model that expresses α-syn under the respiratory condition. We observed striking mitochondrial defects correlated with α-syn accumulation and toxicity. We also identified human and yeast genes that suppress α-syn toxicity and reduce mitochondrial damage. Our data support using a respiratory cell model to study mitochondria-associated α-syn toxicity.

    Committee: Quan Zhong Ph.D. (Advisor); Lynn Hartzler Ph.D. (Committee Member); Hongmei Ren Ph.D. (Committee Member) Subjects: Biology
  • 2. Santhanakrishnan, Rajalakshmi Mitochondria-Dependent Cellular Toxicity of α-synuclein Modeled in Yeast

    Doctor of Philosophy (PhD), Wright State University, 2019, Biomedical Sciences PhD

    Parkinson's disease is the second most common neurodegenerative disease. This disease is caused by the degeneration of dopaminergic neurons, leading to debilitating motor symptoms and early mortality. The protein α-synuclein (α-syn), encoded by SNCA, misfolds and forms inclusions in Parkinson's disease brains. When α-syn is overexpressed in yeast, it causes cellular toxicity and an increased number of aggregates, recapitulating the toxic phenotypes observed in humans and animal models. Yeast models are a powerful tool to perform high-throughput overexpression screening to identify modifiers of α-syn toxicity. α-syn causes mitochondrial dysfunction by inhibiting complex I and inducing mitochondrial fragmentation. Prior screening of α-syn were limited to only the galactose condition, where mitochondrial function is dispensable. Previous screening was performed exclusively with the GAL1 promoter, restricting the genes to only those induced by galactose. We have validated an overexpression system using GAL3 alleles that can induce genes under mitochondrial-dependent glycerol-ethanol condition and other non-galactose conditions (calorie restriction, nitrogen starvation and raffinose). α-syn showed discrepancy in the correlation of toxicity and aggregation in non-galactose conditions. Compared to galactose, under glycerol-ethanol condition, α-syn exhibited higher toxicity, formed more aggregates, and decreased viability and respiratory competency despite having similar expression under the two conditions. We screened 14,827 human gene clones and identified 87 that can suppress α-syn toxicity in glycerol-ethanol. Genes involved in RNA polymerase II function, anterior-posterior axis and nucleoplasm were overrepresented. Among the suppressor hits, we identified four 14-3-3 protein isotypes (β, γ, θ, and ζ). None of the four suppressors suppressed the toxicity under galactose. However, the 14-3-3 suppressors did not reduce aggregates under glycerol-ethanol. No increase in res (open full item for complete abstract)

    Committee: Quan Zhong Ph.D. (Advisor); David R. Cool Ph.D. (Committee Member); Paula Ann Bubulya Ph.D. (Committee Member); David R. Ladle Ph.D. (Committee Member); Weiwen Long Ph.D. (Committee Member) Subjects: Biology; Cellular Biology; Molecular Biology