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2018 Scientific Report

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Center for Neurodegenerative Science GERHARD (Gerry) A. COETZEE, Ph.D. Dr. Coetzee earned his Ph.D. in medical biochemistry from the University of Stellenbosch, South Africa, in 1977. He was a professor in the Departments of Urology, Microbiology, and Preventive Medicine at the Keck School of Medicine at USC before joining VARI as a Professor in November 2015. STAFF Alix Booms, B.S. Kim Cousineau, M.P.A. Steve Pierce, Ph.D. Trevor Tyson, Ph.D. J.C. Vanderschans, B.S. RESEARCH INTERESTS Our laboratory focuses on exploring genome-wide association studies (GWAS) to uncover genetic risk mechanisms in breast cancer and Parkinson’s disease (PD); we call these post-GWAS studies. GWAS of complex phenotypes such as those of breast cancer and PD have become powerful pointers to genetic predisposition. Additionally, as next-generation sequencing techniques have become more feasible and increasingly affordable, mechanisms may be explored genome-wide. A daunting and unexpected finding was that for many complex diseases, more than 90% of the risk single nucleotide polymorphisms (SNPs) are located in noncoding DNA. To address these issues, we and others have used chromatin biofeatures to explore potential functionality. Specifically, our laboratory uses cell culture models to probe mechanisms of risk. Our main hypothesis is that risk resides in enhancers scattered through our genome that are identifiable within chromatin biofeatures (nucleosome occupancy and histone covalent modifications). Enhancers are cell type–specific and mediate risk by specific gene expression control. For example, in one of our projects we used differentiating dopaminergic neurons (Lund human mesencephalic [LUHMES] cells) to probe PD risk enhancers. We matched the differention-specific appearance or disappearance of enhancers with changes in gene expression. We thus identified 22,057 enhancers paired with 6,388 differentially expressed genes by proximity. These enhancers are enriched with 14 transcription factor response elements driving a cluster of genes involved in neurogenesis. We found that differentiated LUHMES cells, but not undifferentiated cells, showed enrichment for PD risk SNPs. Candidate genes for these loci were associated with the processes of synaptic vesicle cycling and transport, which implies that PD-related disruption of these pathways is intrinsic to dopaminergic neurons. We are using gene-editing tools to delve deeply into how they affect genetic predisposition. Understanding of this kind may lead to the identification of preventive strategies against PD. 40 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

JEFFREY H. KORDOWER, Ph.D. Dr. Kordower earned his Ph.D. at City University of New York in 1984. He joined Rush University Medical Center in 1990, where he currently is the Alla V. and Solomon Jesmer Professor of Neurological Sciences and the director of the Rush Research Center for Brain Repair, among other positions. He joined VARI in January 2016 as a Professor and Director's Scholar while continuing his primary appointment at Rush. RESEARCH INTERESTS There is a close collaboration between the Kordower lab and the scientists in the Center for Neurodegenerative Science in trying to understand Parkinson’s disease pathogenesis and to develop novel therapies for the disease. Recently, the lab has been investigating the prion-like transfer of abnormal α-synuclein from cell to cell within the brain. The Kordower lab’s collaborative research program, based at Rush University Medical Center in Chicago, uses insights garnered from this work to design and carry out crucial preclinical studies, a vital step in translating potential therapies into clinical trials for Parkinson’s patients. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 41

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