Leslie M. Thompson
Professor, Psychiatry & Human Behavior
Neurobiology and Behavior
|Human genetic disorders|
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.
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.
Lee JH, Tecedor L, Chen YH, Monteys AM, Sowada MJ, Thompson LM, Davidson BL. (2015). Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron. Jan 21;85(2):303-15. PMID: 25556834
Miller S, Hill Della Puppa G, Reidling J, Marcora E, Thompson LM, Treanor J. (2014). Comparison of phosphodiesterase 10A, dopamine receptors D1 and D2 and dopamine transporter ligand binding in the striatum of the R6/2 and BACHD mouse models of Huntington's disease. J Huntingtons Dis.;3(4):333-41. PMID: 25575954
Liu KY, Shyu YC, Barbaro BA, Lin YT, Chern Y, Thompson LM, James Shen CK, Marsh JL. (2015). Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease. Hum Mol Genet. Mar 15;24(6):1602-16. PMID: 25398943
Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh JL, Housman DE, Thompson LM, Steffan JS (2014). Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. Nov 25;111(47):16889-94. PMID: 25385587
Salazar L, Kashiwada T, Krejci P, Meyer AN, Casale M, Hallowell M, Wilcox WR, Donoghue DJ, Thompson LM (2014). Fibroblast growth factor receptor 3 interacts with and activates TGFß-activated kinase 1 tyrosine phosphorylation and NF?B signaling in multiple myeloma and bladder cancer. PLoS One. Jan 23;9(1):e86470. PMID: 24466111
Mattis VB, Wakeman DR, Tom C, Dodiya HB, Yeung SY, Tran AH, Bernau K, Ornelas L, Sahabian A, Reidling J, Sareen D, Thompson LM, Kordower JH, Svendsen CN (2014). Neonatal immune-tolerance in mice does not prevent xenograft rejection. Exp Neurol. Apr;254:90-8. PMID: 24440640
Vashishtha M, Ng CW, Yildirim F, Gipson TA, Kratter IH, Bodai L, Song W, Lau A, Labadorf A, Vogel-Ciernia A, Troncosco J, Ross CA, Bates GP, Krainc D, Sadri-Vakili G, Finkbeiner S, Marsh JL, Housman DE, Fraenkel E, Thompson LM (2013). Targeting H3K4 trimethylation in Huntington disease.
Proc Natl Acad Sci U S A. Aug 6;110(32):E3027-36. PMID: 23872847
O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, Lee J, Monteys AM, Pallos J, Mee L, Vashishtha M, Apostol BL, Nicholson TP, Illes K, Zhu YZ, Dasso M, Bates GP, Difiglia M, Davidson B, Wanker EE, Marsh JL, Lima CD, Steffan JS, Thompson LM (2013). SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. Jul 25;4(2):362-75. PMID: 23871671
Sontag EM, Joachimiak LA, Tan Z, Tomlinson A, Housman DE, Glabe CG, Potkin SG, Frydman J, Thompson LM (2013).
Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes. Proc Natl Acad Sci U S A. Feb 19;110(8):3077-82. PMID: 23365139
Sontag EM, Lotz GP, Agrawal N, Tran A, Aron R, Yang G, Necula M, Lau A, Finkbeiner S, Glabe C, Marsh JL, Muchowski PJ, Thompson LM (2012). Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models.
J Neurosci. Aug 8;32(32):11109-19. PMID: 22875942
HD iPSC Consortium (2012). Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell. Aug 3;11(2):264-78. PMID: 22748968
Sontag EM, Lotz GP, Yang G, Sontag CJ, Cummings BJ, Glabe CG, Muchowski PJ, Thompson LM (2012). Detection of Mutant Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules.
J Huntingtons Dis. Jun 19;1(1):127-140. PMID: 24086178
Jia H, Pallos J, Jacques V, Lau A, Tang B, Cooper A, Syed A, Purcell J, Chen Y, Sharma S, Sangrey GR, Darnell SB, Plasterer H, Sadri-Vakili G, Gottesfeld JM, Thompson LM, Rusche JR, Marsh JL, Thomas EA (2012). Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease.
Neurobiol Dis. May;46(2):351-61. PMID: 22590724
Pitts A, Dailey K, Newington JT, Chien A, Arseneault R, Cann T, Thompson LM, Cumming RC (2012). Dithiol-based compounds maintain expression of antioxidant protein peroxiredoxin 1 that counteracts toxicity of mutant huntingtin. J Biol Chem. Jun 29;287(27):22717-29. PMID: 22577145
Strong MK, Southwell AL, Yonan JM, Hayden MR, Macgregor GR, Thompson LM, Steward O (2012).
Age-Dependent Resistance to Excitotoxicity in Htt CAG140 Mice and the Effect of Strain Background. J Huntingtons Dis.;1(2):221-241. PMID: 23833693
|Miller J, Arrasate M, Brooks E, Libeu CP, Legleiter J, Hatters D, Curtis J,Cheung K, Krishnan P, Mitra S, Widjaja K, Shaby BA, Lotz GP, Newhouse Y, Mitchell EJ, Osmand A, Gray M, Thulasiramin V, Saudou F, Segal M, Yang XW, Masliah E, Thompson LM, Muchowski PJ, Weisgraber KH, Finkbeiner S. (2011). Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat Chem Biol;7:925-34. PubMed PMID: 22037470;|
|Bodai, L., Pallos, J. Thompson, L.M. and Marsh, J.L. (2011). Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington’s Disease. Neurodegenerative Disease 9:104-6 PubMed PMID: 21912091|
|Lotz, G.P., Legleiter, J., Aron, R., Mitchell, E.J., Huang, S-Y, Ng, C., Glabe, C. Thompson, L.M. and Muchowski, P. J. (2010). Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J. Biol. Chem. 285:38183-93.|
|McConoughey, S.J., Basso, M., Niatsetskaya, Z.V., Sleiman, S.F., Smirnova, N., Langley, B.C., Mahishi, L., Cooper, A.J.L., Antonyak, M.A., Cerion, R.A., Li, B., Starkov, A., Chaturvedi, R., Beal, M.F., Coppola, G., Geschwind, D.H., Ryu H., Li, X., Lismaa, S., Pallos, J., Pasternack, R., Hils, M., Fan, J., Raymond, L.A., Marsh, J.L., Thompson, L.M. and Ratan, R.R. (2010). Inhibition of transgultaminase 2 mitigates transcriptional dysregulation in mouse models of Huntington disease. EMBO Mol. Med. 2: 349-70|
|Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith DL, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell MM, Reeves SA, Bates GP, Neri C, Thompson LM, Marsh JL, Kazantsev AG. (2010). SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc. Natl. Acad. Sci USA 107:7927-32.|
|Legleiter, J. Mitchell, E. Lotz, G.P., Sap, E., DiFiglia, M. Thompson, L.M. and Muchowski, P.J. (2010). Mutant Huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J. Biol. Chem.285:14777-90.|
|Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan JS, Thompson LM, Wetzel R, Yang XW. (2009). Serines 13 and 16 are critical determinants of full length human mutant huntingtin induced disease pathogenesis in HD Mice. Neuron 64:828-840.|
|Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O'Rourke J.G., Khashwji H, Lukacsovich T, Zhu YZ, Lau AL, Massey A, Hayden MR, Zeitlin SO, Finkbeiner S, Green KN, LaFerla, F.M., Bates G, Huang L, Patterson PH, Lo DC, Cuervo AM, Marsh JL, Steffan JS. (2009). IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome, J. Cell Bio. 187:1083-1099.|
|Aiken, C.T., Steffan, J.S., Guerrero, C.M., Khashwji, H. Lukacsovich, T., Simmons, D., Pucell, J.M. Menhaji, K., Zhu, YZ, Green, K., LaFerla, F., Huang, L. Thompson, L.M., Marsh, J.L. (2009). Phosphorylation of threonine 3: implications for Huntingtin aggregation and toxicity. J. Biol. Chem. 284:29427-29436|
|Salazar, L, Kashiwada, K., Krejci, P, Muchowski, P., Donoghue, D., Wilcox, W.R., and Thompson, L.M. (2009). A Novel Interaction between Fibroblast Growth Factor Receptor 3 and the p85 Subunit of Phosphoinositide 3-Kinase; Activation-dependent Regulation of ERK by p85 in Multiple Myeloma Cells. 18:1951-1961|
|Marsh, J.L., Lukacsovich, T., and Thompson, L.M. (2009). Animal models of polyglutamine diseases and therapeutic approaches. J. Biol. Chem. 284, 7431-5.|
|Krejci, P., Salazar, L., Kashiwada, T.A., Chlebova, K., Salasova, A. Thompson, L.M., Bryja, V., Kozubik, A., Wilcox, W. (2009). Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PlosOne 3(12):3961.|
|Krejci P., Prochazkova J., Bryja V., Jelinkova P., Pejchalova K., Kozubik A., Thompson LM, Wilcox WR. (2009). Fibroblast growth factor inhibits interferon gamma-STAT1 and interleukin 6-STAT3 signaling in chondrocytes. Cell Signal. 21, 151-60.|
|Kazantsev, A.G. and Thompson, L.M. (2008). Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Rev Drug Disc. 7, 1-15|
|Green, K., Steffan, J.S., Martinez-Coria, H., Sun, X., Schreiber, S., Thompson, L.M., and LaFerla, F. (2008). Nicotinamide restores cognition in AD transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J. Neurosci. 28, 11500-11510.|
|Pallos, J., Bodai, L., Lukacsovich, T., Purcell, J.M., Steffan, J.S., Thompson, L.M. and Marsh, J.L. (2008). Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum. Mol. Genet. 17, 3767-3775.|
|Thompson, L.M. (2008). Neurodegeneration: a question of balance. Nature 452, 707-708.|
|Conforti, P., Ramos, C., Apostol, B.L., Simmons, D.A. Nguyen, H., Riess, O., Thompson, L.M., Zuccato, C. and Cattaneo, E. (2008). Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington’s disease: restoration by the neuroprotective compound CEP-1347. Mol. Cell. Neurosci. 39, 1-7.|
|Apostol, B.L., Simmons, D.A., Zuccato, C., Illes, K., Pallos, J., Casale, M., Conforti, P., Ramos, C., Roarke, M., Kathuria, S., Cattaneo, E., Marsh, J.L. and Thompson, L.M.. (2008). CEP-1347 suppresses mutant Huntingtin-associated neurotoxicity in cell, Drosophila and mouse models of HD and restores brain derived neurotrophic factor levels in R6/2 mice. Mol. Cell. Neurosci. 39, 8-20. *co-senior authors|
|McLin, J.P., Thompson, L.M., Lusis, A.J., Davis, R.C. and Steward, O. (2008). Genes on distal chromosome 18 determine vulnerability to excitotoxic neurodegeneration following status epilepticus, but not striatal neurodegeneration induced by quinolinic acid. Neurobiol. of Disease 29, 391-399.|
|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.|
|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.|
|Jia, H., Pallos, J., Jacques, V., Lau, A., Tang, B., Cooper, A., Syed, A., Purcell, J., Chen, Y., Sharma, S., Sangrey, G.R., Darnell, S.B., Plasterer, H., Sadri-Vakili, G., Gottesfeld, J., Thompson, L.M., Rusche, J.R., Marsh, J.L., and Thomas, E.A. (2012). Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease. Neurobiol of Disease 46: 351–361.|
|Sleiman SF, Langley BC, Basso M, Berlin J, Xia L, Payappilly JB, Kharel MK, Guo H, Marsh JL, Thompson LM, Mahishi L, Ahuja P, MacLellan WR, Geschwind DH, Coppola G, Rohr J, Ratan RR. (2011). Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci. 31:6858-70. PubMed PMID: 21543616.|
|Sinadinos C, Burbidge-King T, Soh D, Thompson L, Marsh L, Wyttenbach A, and Mudher AK. (2009). Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons. Neurobiol Dis. 34:389-395.|
|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.|
|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.|
Society for Neuroscience
American Society of Human Genetics
1996-2000 Hereditary Disease Foundation, Venezuela Huntington’s Disease Project Participant
Interdepartmental Neuroscience Program
Cellular and Molecular Biosciences
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