11 months ago

2018 Scientific Report

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  • Institute
  • Biology
  • Methylation
  • Molecular
  • Mechanisms
  • Epigenetic
  • Michigan
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Center for

Center for Neurodegenerative Science DARREN J. MOORE, Ph.D. Dr. Moore earned a Ph.D. in molecular neuroscience from the University of Cambridge, U.K., in 2001 in the laboratory of Piers Emson. He was at Johns Hopkins University and the Swiss Federal Institute of Technology (EPFL) in Lausanne before joining the VARI faculty as an Associate Professor in early 2014. He was promoted to Professor in 2017. STAFF Xi Chen, Ph.D. Madalynn Erb, Ph.D. Emily Glidden, B.S. Md Shariful Islam, Ph.D. Jennifer Kordich, M.S. Nate Levine, B.S. An Phu Tran Nguyen, Ph.D. STUDENTS Lindsey Cunningham, B.S. Allie Weber, B.S. Erin Williams, B.A. RESEARCH INTERESTS Our laboratory studies the molecular pathogenesis of Parkinson’s disease, with the long-term goal of developing novel, targeted, disease-modifying therapies and neuroprotective strategies. Although most cases of PD are sporadic, 5–10% of cases are inherited, with causative mutations identified in at least 13 genes. We focus on the cell biology and pathophysiology of several proteins that cause inherited PD, including the dominantly inherited LRRK2 (leucine-rich repeat kinase 2, a multidomain protein with GTPase and kinase activity) and VPS35 (vacuolar protein sorting 35 ortholog, a component of the retromer complex), and the recessive proteins parkin (an E3 ubiquitin ligase), synaptojanin-1 (an endosomal lipid phosphatase), and ATP13A2 (a lysosomal P5B-type ATPase). We seek to explain the normal biological function of these proteins in the mammalian brain and the molecular mechanisms through which disease-associated variants produce neuronal dysfunction and eventual neurodegeneration in inherited forms of Parkinson’s. We employ a multidisciplinary approach that combines molecular, cellular, and biochemical techniques in experimental model systems such as human cell lines, primary neuronal cultures, Saccharomyces cerevisiae, nematodes, fruit flies, rodents, and human brain tissue. We have developed several unique rodent models (transgenic, knock-out, knock-in) for mechanistic studies of proteins. Some of our current projects focus on • the contribution of enzymatic activity and protein aggregation to neurodegeneration in novel, adenoviral-based, LRRK2 rodent models of PD; • neuroprotective effects of pharmacological kinase inhibition in LRRK2 rodent models; • genome-wide identification of genetic modifiers of LRRK2 toxicity in S. cerevisiae; • identification of novel GTPase effector proteins and kinase substrates for LRRK2; • the role of ArfGAP1 in mediating LRRK2-induced neurotoxic pathways; • the functional interaction of LRRK2 with other PD-linked proteins (ATP13A2 and synaptojanin-1); and • the development of novel rodent models of VPS35-linked PD and the pathological interactions of VPS35 with α-synuclein and LRRK2. Leslie Wyman, B.S. 44 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

RECENT CENTER PUBLICATIONS Amos, Christopher I., Joe Dennis, Zhaoming Wang, Jinyoung Byun, Frederick R. Schumacher, Simon A. Gayther, Graham Casey, David J. Hunter, Thomas A. Sellers, Stephen B. Gruber, Alison M. Dunning, . . . , Gerhard A. Coetzee, Dennis J. Hazelett, . . ., and Douglas F. Easton. 2017. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer, Epidemiology, Biomarkers & Prevention 26(1): 126–135. Brundin, Patrik, Kuldip D. Dave, and Jeffrey H. Kordower. 2017. Therapeutic approaches to target alpha-synuclein pathology. Experimental Neurology 298 (Pt. B): 225–235. Bryleva, E.Y., S.A. Keaton, J. Grit, Z. Madaj, A. Sauro-Nagendra, L. Smart, S. Halstead, E. Achtyes, and L. Brundin. 2017. The acute-phase mediator serum amyloid A is associated with symptoms of depression and fatigue. Acta Psychiatrica Scandinavica 135(5): 409–418. Espay, Alberto, Patrik Brundin, and Anthony E. Lang. 2017. Precision medicine for disease modification in Parkinson disease. Nature Reviews Neurology 13(2): 119–126. Fernström, Johan, Åsa Westrin, Cécile Grudet, Lil Träskman-Bendz, Lena Brundin, and Daniel Lindqvist. 2017. Six autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters. PLoS One 12(4): e0176358. Islam, Md. Shariful, and Darren J. Moore. 2017. Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation. Biochemical Society Transactions 45(1): 163–172. Jakubowski, Jennifer L., and Viviane Labrie. 2017. Epigenetic biomarkers for Parkinson’s disease: from diagnostics to therapeutics. Journal of Parkinson’s Disease 7(1): 1-12. Killinger, Bryan Andrew, and Viviane Labrie. 2017. Vertebrate food products as a potential source of prion-like α-synuclein. npj Parkinson’s Disease 3: 33. Labrie, Viviane, and Patrik Brundin. 2017. Alpha-synuclein to the rescue: immune cell recruitment by alpha-synuclein during gastrointestinal infection. Journal of Innate Immunity 9(5): 437–440. Nguyen, An Phu Tran, Guillaume Daniel, Pamela Valdés, Md Shariful Islam, Bernard L. Schneider, and Darren J. Moore. In press. G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain. Human Molecular Genetics. Nguyen, An Phu Tran, and Darren J. Moore. 2017. Understanding the GTPase activity of LRRK2: regulation, function, and neurotoxicity. In Leucine-rich Repeat Kinase 2 (LRRK2), Hardy J. Rideout, ed. Advances in Neurobiology series, Vol. 14. Cham, Switzerland: Springer, pp. 71-88. Oh, Edward, Richie Jeremian, Gabriel Oh, Daniel Groot, Miki Susic, KwangHo Lee, Kelly Foy, Peter W. Laird, Arturas Petronis, and Viviane Labrie. 2017. Transcriptional heterogeneity in the lactase gene within cell-type is linked to the epigenome. Scientific Reports 7: 41843. Pierce, Steven, and Gerhard A. Coetzee. 2017. Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One 12(4): e0175882. Rey, Nolwen L., Sonia George, Jennifer A. Steiner, Zachary Madaj, Kelvin C. Luk, John Q. Trojanowski, Virginia M.-Y. Lee, and Patrik Brundin. In press. Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathologica. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 45

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