Shu G. Chen, PhD Research & Impact Research Investigators Shu G. Chen, PhD Investigator: Shu G. Chen, PhD Name of Institution: Case Western Reserve University, Cleveland, Ohio Project Title: Novel knock-in models linking Rab phosphorylation to neurodegeneration in Parkinson’s disease (PD) Investigator Bio: Dr. Shu G. Chen is an Associate Professor of Pathology and Neurology at Case Western Reserve University School of Medicine. He received his PhD from the State University of New York at Buffalo. His research centers on the pathogenesis of PD and other neurodegenerative disorders. His laboratory aims to understand the molecular mechanisms through which the protein kinase LRRK2 modulates neuronal function and causes neurodegeneration in PD. Objective: To develop an animal model to understand how abnormal phosphorylation of Rab proteins by LRRK2 leads to neuronal dysfunction and neurodegeneration. Background: Protein kinases are enzymes which add phosphate groups onto other proteins, thereby regulating the function of the protein substrates. Recent studies have shown that PD-causing mutations in LRRK2 enhance its kinase activity and increase phosphorylation of a group of proteins called Rab proteins. The consequence of Rab phosphorylation by LRRK2 is not known. Methods/Design: By adding a phosphate group onto the Rab proteins, the Rab proteins acquire an extra negative charge, which can be mimicked in the laboratory by genetically engineering the Rab proteins. The nematode, or roundworm, C. elegans is a well-established model organism for investigating molecular mechanisms underlying neurodegeneration in PD. We will utilize a newly developed genome editing technology known as CRISPR-Cas9 to rapidly generate C. elegans which carry the altered Rab proteins. We will examine whether the C. elegans with the abnormal Rab proteins manifest neurological defects, and if so, investigate the underlying mechanisms that contribute to the defects. Relevance to Diagnosis/Treatment of Parkinson’s disease: Availability of this type of animal models will facilitate the identification of genetic and biochemical contributors to neurodegeneration, thereby leading to the future development of PD therapeutics.