Leslie M. ThompsonProfessor, Psychiatry & Human Behavior Director, Interdepartmental Neuroscience Program Neurobiology and Behavior Biological Chemistry |
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Research Interests |
Human genetic disorders | |
| URL | faculty.uci.edu/profile.cfm?faculty_id=4708 | |
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Academic Distinctions |
Kivie Moldave Graduate Student Award, Department of Biological Chemistry (1988), Hereditary Disease Foundation Postdoctoral Fellowship (1989-90), National Medical Research Award of the National Health Council (1993), Kaiser-Permanente Excellence in Teaching (1996), Hereditary Disease Foundation Lieberman Award (1997-1999), UCI College of Medicine, Health Science Partners (1999), UCI College of Medicine, AMWA Gender Equity Award (1999), UCI College of Medicine, Silver Beaker award to the Outstanding Basic Science Faculty Member (1999), Hereditary Disease Foundation Scientific Advisory Board (2000-2007), Huntington's Disease Society of America Coalition for the Cure Investigator (2001-present), Distinguished Assistant Professor Award for Research, UC Irvine (2002), Huntington’s Disease Society of America Distinguished Leadership Award (2002), UCI College of Medicine, Excellence in Teaching (2004, 2005, 2006, 2007), 2006 Office of Educational Affairs MVP Outstanding Service Award, 2006-present standing member CMND NIH study section, 2005-present F1000 Neurological Disorders Faculty, 2007 Fellow, Center for Learning and Memory. |
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Research Abstract |
Discoveries in human genetics have allowed investigators to make significant progress in understanding the underlying cellular mechanisms that are disrupted by these mutations and to develop rational therapeutics. The research in the Thompson lab has largely focused on understanding pathogenic mechanisms for neurodegenerative disease and FGFR3-associated cancers in order to identify and validate novel therapeutic targets for treatment of these diseases. HD is an autosomal dominant neurodegenerative disease characterized by specific regions of neuronal dysfunction and loss, most notably of neurons in the striatum and cortex. There is currently no effective treatment or cure for this devastating disorder. The primary cause of HD is the expansion of a CAG triplet repeat encoding a polyglutamine (polyQ) tract within the amino terminal portion of a predominantly extranuclear protein, Huntingtin (Htt). Work from our lab and others suggest that this mutation disrupts many cellular processes, including transcriptional regulation, vesicular trafficking, mitochondrial function, degradation pathways, protein modification, protein folding and processing pathways. Protein aggregates and inclusions in affected brain regions, presumably the consequence of abnormal protein folding and/or proteolytic cleavage and degradation of the polyQ repeat-containing protein, are common hallmarks in all polyQ disorders. Cleavage of full-length Htt appears to be an important step in pathogenesis, as does subsequent nuclear accumulation of mutant Htt. Understanding the molecular basis of neuronal dysfunction and death as a consequence of CAG repeat expansion, which appears to confer a dominant toxicity, is critical to development of effective therapies. The molecular and cellular basis of HD pathogenesis is studied using multidisciplinary systems including in vitro, cell culture, Drosophila and mouse models. In collaboration with Dr. J. Lawrence Marsh at UCI, a Drosophila model to study triplet repeat pathogenesis is effective at modeling disease pathogenesis and is part of a long standing collaboration between the two labs. Approaches to investigate neuronal dysfunction include targeted studies of Htt oligomerization and its role in neurotoxicity, transcriptional dysregulation in the context of chromatin remodeling and epigenetics, protein modifications of the mutant protein that influences its clearance and cellular localization, and altered signal transduction in HD. Together with Dr. Joan Steffan at UCI, we are focusing upon the role of post-translational modifications of the Htt protein in cellular localization, transcription and protein clearance. Genetic and pharmacologic approaches to develop therapeutics are active areas of research using each of these systems. However, since molecular commonalities such as defective signal transduction, aggregation and altered transcription have emerged for diseases that involve aberrant protein folding such as Alzheimer’s disease, these efforts have applications to a wide range of neurodegenerative diseases. Aberrant expression of wild-type or hyperactive fibroblast growth factor receptor 3 (FGFR3), a member of a family of receptor tyrosine kinases that function in a broad spectrum of cellular processes, is associated with a number of human cancers including hematologic cancers such as multiple myeloma (MM). The pathogenesis of FGFR3-mediated MM is the focus of fairly recent work in the lab, Dysregulation of FGFR3 appears to be oncogenic, since aberrant growth and survival of tumor cells is related to increased activation of FGFR3 and downstream signaling pathways. Concurrent with disease progression, a subset of these develop activating mutations in FGFR3 which appear to confer an adverse prognosis; these mutations are identical to those in TD. We are using both unbiased and hypothesis driven approaches to understand the mechanisms involved in FGFR3-associated pathophysiology and to identify therapeutic approaches. Specifically, novel protein interactors and signaling pathways for FGFR3 identified through yeast two-hybrid screening are under investigation. |
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| Publications | P. Krejci, B. Masri, L. Salazar, C. Farrington-Rock, H. Prats, L.M. Thompson, and W.R. Wilcox (2007). Bisindolylmaleimide I suppresses FGF-mediated activation of ERK map kinase in chondrocytes by preventing SHP2 association with the FRS2 and GAB1 adaptor proteins. J. Biol. Chem. 282, 929-2936. | |
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E. Rockabrand, N. Slepko, A. Pantalone, V.N. Nukala, A. Kazantsev, J.L. Marsh, P.G. Sullivan, J.S. Steffan, S.L. Sensi, L.M. Thompson (2007). The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum. Mol. Genet. 16, 61-77. 53. P. Krejci, B. Masri, L. Salazar, C. Farrington-Rock, H. Prats, L.M. Thompson, and W.R. Wilcox (2007). Bisindolylmaleimide I suppresses FGF-mediated activation of ERK map kinase in chondrocytes by preventing SHP2 association with the FRS2 and GAB1 adaptor proteins. J. Biol. Chem. 282, 929-2936. |
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| B.L. Apostol, K. Illes, J. Pallos, L. Bodai, J. Wu, A. Strand, E. Schweitzer, J.M. Olson, A. Kazantsev, J.L. Marsh, and L.M. Thompson (2006). Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15, 273-285. | ||
| The U.S.-Venezuela Collaborative Research Project* and Nancy S. Wexler (2004). Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl. Acad. 101:3498-3503. *list of authors. | ||
| J.S. Steffan, N. Agrawal, J. Pallos, E. Rockabrand, L.C. Trotman, N. Slepko, K. Illes, T. Lukacsovich, Y.-Z. Zhu, E. Cattaneo, P.P. Pandolfi, L.M. Thompson*, and J.L.Marsh*. (2004). Huntingtin is SUMO-1 Modified: Implications for Huntington’s Disease Pathogenesis. Science 304: 100-104. | ||
| E. Hockly, V.M. Richon, B. Woodman, D.L. Smith, X. Zhou, E. Rosa, K. Sathasivam, S. Chazi-Noori, A. Mahal, P. Lowden, J.S. Steffan, J.L. Marsh, L.M. Thompson, C.M. Lewis, P.A. Marks and G.P. Bates (2003). Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 100, 2041-2046. | ||
| Kazantsev, H.A. Walker, N. Slepko, J.E. Bear, E. Preisinger, J.S. Steffan, Y-Z. Zhu, F.B. Gertler, D.E. Housman, J.L. Marsh and L.M. Thompson (2002). A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat. Genet. 30, 367-376. | ||
| J. S. Steffan, L. Bodai, J.Pallos, M. Poelman, B. L. Apostol, A. Kazantsev, E. Schmidt, Y.-Z. Zhu, M. Greenwald, R. Kurokawa, D.E. Housman, G.R. Jackson, J. L. Marsh. and L.M. Thompson (2001). Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739-743. | ||
| J. S. Steffan, A. Kazantsev, O. Spasic-Boskovic, M. Greenwald, Y-Z Zhu, H. Gohler, E. Wanker, G.P. Bates, D.E. Housman and L.M. Thompson (2000). The Huntington’s disease protein interacts with p53 and CBP and represses transcription. Proc. Natl. Acad. Sci USA 97, 6763-6768. | ||
| L. Marsh, H. Walker, H. Theissen, Y-Z. Zhu, T. Fielder, and L.M. Thompson (2000). Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9,13-25. | ||
| R. Shiang*, L.M. Thompson*, Y.Z. Zhu, T. Fielder, D. Church, S. Winoker and J.J. Wasmuth (1994). Mutations in the Transmembrane Domain of FGFR3 Cause the Most Common Genetic Form of Dwarfism, Achondroplasia. Cell 78, 335-342. | ||
| Huntington’s Disease Collaborative Research Group (1993). A Novel Gene Containing a Trinucleotide Repeat That is Expanded and Unstable on Huntington’s Disease Chromosomes. Cell 72, 971-983. | ||
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Professional Societies |
Society for Neuroscience American Society of Human Genetics |
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| Other Experience |
1996-2000 Hereditary Disease Foundation, Venezuela Huntington’s Disease Project Participant |
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| Graduate Programs |
Interdepartmental Neuroscience Program Cellular and Molecular Biosciences |
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| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=4708 | |
| Last updated | 12/09/2008 | |