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2018 Scientific Report

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  • Institute
  • Biology
  • Methylation
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  • Epigenetic
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Center for

Center for Neurodegenerative Science VIVIANE LABRIE, Ph.D. Dr. Labrie received her Ph.D. in genetics and neuroscience from the University of Toronto. She was an assistant professor at University of Toronto before joining VARI in early 2016. STAFF Emily Glidden, B.S. Bryan Killinger, Ph.D. Peipei Li, Ph.D. Lee Marshall, Ph.D. RESEARCH INTERESTS Our goal is to gain an in-depth understanding of the primary molecular causes of Alzheimer’s disease and Parkinson’s disease in order to help develop new treatments. Specifically, we study epigenetic involvement in these neurodegenerative illnesses. Epigenetic marks such as methyl or acetyl groups control gene activities without changing the DNA sequence. Such marks are partially stable, that is, they can change in response to environmental signals and over time. This dynamic aspect is highly relevant, because advanced age is the best-known risk factor for both Alzheimer’s and Parkinson’s disease. It takes years before symptoms arise in patients, and after disease onset, the pathological features and symptoms worsen with time. We propose that aberrant epigenetic changes, accumulating with age at key genomic regions, contribute to the etiology of these diseases. We perform genome-wide searches for epigenetic abnormalities in genomic regulatory elements such as enhancers, which affect the complex spatial and temporal expression of genes. Under the influence of regulatory elements, genes can be highly expressed in certain tissues or cell types but weakly or not at all in others. By activating or repressing regulatory elements, epigenetic marks can modify the abundance, timing, and cell-specific patterns of gene expression, which are central to healthy brain function. By applying epigenomic and next generation sequencing–based techniques to human samples, we aim to identify epigenetically misregulated regulatory elements in Alzheimer’s and Parkinson’s disease. We also study the interaction between DNA sequence factors (SNPs) and epigenetic marks to determine whether certain disease-risk variants help coordinate such misregulation. Once we identify disturbed regulatory elements, functional studies will help us understand how they contribute to disease susceptibility. We look for changes in 3D chromatin conformation and in gene transcripts to identify the genes and pathways affected. We also use CRISPR-Cas9 genome editing in cell lines and mice to determine the contribution of epigenetically disrupted regulatory elements to disease pathology and symptoms. Through this research, we can uncover new genomic regions causally involved in Alzheimer’s and Parkinson’s disease. 42 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

JIYAN MA, Ph.D. Dr. Ma earned his Ph.D. in biochemistry and molecular biology from the University of Illinois at Chicago. He was at Ohio State University from 2002 until he joined VARI in November 2013 as a Professor. STAFF Romany Abskharon, Ph.D. Katelyn Becker, M.S. Emily Glidden, B.S. Amandine Roux, Ph.D. Juxin Ruan, Ph.D. Fei Wang, Ph.D. Xinhe Wang, Ph.D. RESEARCH INTERESTS Protein aggregation is a key pathological feature of a large group of late-onset neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Our overall goals are to uncover the molecular events leading to protein misfolding in the aging central nervous system; to understand the relationship between misfolded protein aggregates and neurodegeneration; and to develop approaches to prevent, halt, or reverse protein aggregation and neurodegeneration in these devastating diseases. We study protein aggregates in prion diseases (transmissible spongiform encephalopathies). These are true infectious diseases that can spread from individual to individual and cause outbreaks. We have established an in vitro system to reconstitute prion infectivity with bacterially expressed prion protein plus defined cofactors. We use this system to dissect the essential components and the structural features of an infectious prion and to uncover the molecular mechanisms responsible for the prion strain and species barrier. Recently, the concept of prions has expanded to Parkinson’s and Alzheimer’s diseases. α-Synuclein has been suggested to spread the disease pathology in a prion-like manner from a sick cell to healthy ones. We want to understand the similarities and differences between prions and amyloidogenic proteins such as α-synuclein. We are investigating cellular factors that affect α-synuclein aggregation and the connections between various α-synuclein aggregated forms, their prion-like spread, and dopaminergic neuron degeneration. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 43

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