Master of Science (MS), Wright State University, 2018, Biological Sciences

Optineurin, an autophagy adaptor protein genetically linked to Normal Tension Glaucoma and Amyotrophic Lateral Sclerosis, has been found in the pathological inclusions of various other neurodegenerative disorders, supporting an important role of optineurin in neurodegeneration. Using yeast as a model, we found that overexpression of optineurin drastically enhances the toxicity of the Parkinson's disease-causing protein, alpha-synuclein. Considering the conserved protein-protein interaction between optineurin and Ypt1, a yeast suppressor of the toxicity of both optineurin and alpha-synuclein, we hypothesize that cellular targets of optineurin underlie in the cytotoxicity and the enhancer effect. Using genome-wide yeast two-hybrid screens, we identified 97 yeast interacting proteins of optineurin and systematically tested their modifier effect on the toxicity of optineurin and alpha-synuclein. Given the neuroprotective effect of the mammalian homologs of Ypt1, the convergent pathways of the identified modifiers may represent conserved cellular perturbations induced by optineurin overexpression in higher eukaryotes.

Committee: Quan Zhong Ph.D. (Advisor); Mill Miller Ph.D. (Committee Member); Paula Bubulya Ph.D. (Committee Member) Subjects: Cellular Biology; Genetics; Neurosciences