J. Lawrence Marsh, Ph.D.

Developmental genetics The Marsh lab is currently focused on two problems.

In one project, we are interested in the mechanisms of late onset neurodegeneration in man with particular focus on the polyglutamine diseases including Huntington’s Disease. We have humanized flies by inserting mutant human disease genes such as the Huntington’s gene into flies and find that one can mimic the pathology seen in man with good fidelity. This model has been used to explore mechanisms of degeneration and to identify therapeutic strategies and pharmaceutical agents that can ameliorate this devastating disease and speed the testing of effective therapeutics in mammals. In particular, we have found that modulators of transcriptional activity including the Histone DeACetylases (HDACs) can be productively targeted to ameliorate disease severity. We are exploring the role of other transcription modifying loci as well as the role of post-translational modifications in modulating Huntington’s Disease.

In our other project, we are interested in understanding how tissues become organized into coherent structures during patterning. It is clear that secreted signaling molecules (morphogens) play a key role in tissue patterning. Using genetic strategies in Drosophila, we find that the regulatory networks between morphogens can generate a robust self-organizing system that involves autoactivation and cross inhibition. The regulatory network between Wingless (Wg or Wnt in vertebrates) and Decapentaplegic (Dpp, a relative of the Bone Morphogenetic Family of proteins) that drives development of the fly leg is such an example. We are studying the mechanism of cross signaling in this self-organizing system. While such a system is elegant, it is clear that corruption of such a network by mutation is a recipe for cancer. In collaboration with others, we have extended these studies by finding that human tissues employ similar networks of regulation in tissues such as the colon and breast. We are currently investigating the molecular consequences of oncogenic mutations in these pathways and the regulation of the down stream transcription factors (TCFs) that transduce these signals.

Recent Publications

  • Liu, K. Y., Y. C. Shyu, B. A. Barbaro, Y. T. Lin, Y. Chern, L. M. Thompson, C. K. James Shen and J. L. Marsh (2014). “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 24(6): 1602-1616
  • Barbaro, B.A., Lukacsovich, T., Agrawal, N., Burke, J., Bornemann, D.J., Purcell, J.M., Worthge, S., Caricasole, A., Weiss, A., Song, W., Morozova, O.A., Colby, D.W., and Marsh, J.L. (2014). Comparative study of naturally occurring huntingtin fragments in Drosophila points to Exon 1 as the most pathogenic species in Huntington’s Disease. Hum Mol Genet 24:913-925.
  • Ochaba, J., Lukacsovich, T., Csikos, G., Zheng, S., Margulis, J., Salazar, L., Mao, K., Lau, A.L., Yeung, S.Y., Humbert, S., Saudou, F., Klionsky, D.J., Finkbeiner, S., Zeitlin, S.O., Marsh, J.L., Housman, D.E., Thompson, L.M., Steffan, J.S., 2014. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A 111, 16889-16894
  • Smith, M.R., Syed, A., Lukacsovich, T., Purcell, J., Barbaro, B.A., Worthge, S.A., Wei, S.R., Pollio, G., Magnoni, L., Scali, C., Massai, L., Franceschini, D., Camarri, M., Gianfriddo, M., Diodato, E., Thomas, R., Gokce, O., Tabrizi, S.J., Caricasole, A., Landwehrmeyer, B., Menalled, L., Murphy, C., Ramboz, S., Luthi-Carter, R., Westerberg, G., Marsh, J.L., 2014. A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet 23, 2995-3007.
  • O’Rourke JG, Gareau JR, Ochaba J, Song W, Rasko 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 reports. 4:362-75.
  • Song W, Smith MR, Syed A, Lukacsovich T, Barbaro BA, Purcell J, Bornemann DJ, Burke J, Marsh JL. (2013) Morphometric analysis of Huntington’s disease neurodegeneration in Drosophila. Methods in molecular biology. 1017:41-57.
  • 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. 110:E3027-36
  • Sontag, E. M., Lotz, G. P., Agrawal, N., Tran, A., Aron, R., Yang, G., Necula, M., Lau, A., Finkbeiner, S., Glabe, C., Marsh, J. L., Muchowski, P. J. and Thompson, L. M.  (2012). “Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models.” J Neurosci 32(32): 11109-11119.
  • Jia, H., Tang, B., Pallos, J., Cooper, A., Chen, Y., Jacques, V., Plasterer, H., Rusche, J., Gottesfeld, J., Marsh, J. L. and Thomas, E. (2012) ‘Histone deacetylase (HDAC) inhibitors targeting HDAC1 and HDAC3 ameliorate polyglutamine-elicited phenotypes in Drosophila and mouse models of Huntington’s disease’, Neurobiology of Disease 46, 351-61.
  • Bodai, L. and Marsh, J. L. (2012) A crucial target in Huntington’s disease: ERK at the crossroads of signaling, Bioessays  In Press.
  • 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 Diseases In Press:  Ms #: 201101006
  • Sleiman, S. F., Langley, B. C., Basso, M., Berlin, J., Xia, L., Payappilly, J. B., Kharel, M. K., Guo, H. C., Marsh, J. L., Thompson, L. M., Mahishi, L., Ahuja, P., MacLellan, W. R., Geschwind, D. H., Coppola, G., Rohr, J. and Ratan, R. R. (2011)  Mithramycin Is a Gene-Selective Sp1 Inhibitor That Identifies a Biological Intersection between Cancer and Neurodegeneration, Journal of Neuroscience 31(18): 6858-6870.
  • Maher, P., Dargusch, R., Bodai, L., Gerard, P. E., Purcell, J. M. and Marsh, J. L. (2011). ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington’s disease. Hum Mol Genet 20, 261-70.  PMID:20952447 [PubMed – in process] PMCID: PMC3005900
  • Ossato, G., Digman, M.A., Aiken, C., Lukacsovich, T., Marsh, J.L., Gratton, E. (2010) A two-step path to inclusion formation of huntingtin peptides revealed by number and brightness analysis. Biophys J. 98(12):3078-85
  • Thompson, L.M., Aiken, C.T., Kaltenbach, L.S., Agrawal, N., Illes, K., Khoshnan, A., Martinez-Vincente, M., Arrasate, M., O’Rourke, J.G., Khashwji, H., Lukacsovich, T., Zhu, Y.Z., Lau, A.L., Massey, A., Hayden, M.R., Zeitlin, S.O., Finkbeiner, S., Green, K.N., LaFerla, F.M., Bates, G., Huang, L., Patterson, P.H., Lo, D.C., Cuervo, A.M., Marsh, J.L., and Steffan, J.S. (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol. 187(7):1083-99. Epub 2009 Dec 21
  • Aiken, C.T., Steffan, J.S., Guerrero, C.M., Khashwji, H., Lukacsovich, T., Simmons, D., Purcell, J.M., Menhaji, K., Zhu, Y.Z., Green, K., Laferla, F., Huang, L., Thompson, L.M., and Marsh, J.L. (2009) Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem. 284(43):29427-36. Epub 2009 Aug 26.
  • Marsh, J.L., Lukacsovich, T., Thompson, L.M. (2009) Animal models of polyglutamine diseases and therapeutic approaches. J Biol Chem. 284(12):7431-5. Epub 2008 Oct 28. Review.
  • Apostol, B.L., Simmons, D.A., Zuccato, C., Illes, K., Pallos, J., Casale, M., Conforti, P., Ramo, C., Roarke, M., Kathuria, S., Cattaneo, E., Marsh, J.L., and Thompson, L.M. (2008) CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice. Mol Cell Neurosci. 39(1):8-20. Epub 2008 Apr 24.
  • Iron,D, Syed, A, Theisen, H, Lukacsovich, T, Naghibi, M, Marsh, J.L., Wan, FYM, and Nei,Q. (2008) The role of feedback in the formation of morphogen territories. Mathematical biosciences and engineering Volume 5, 277-298 PMID: 18613734
  • 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
  • Marsh, J.L., Lukacsovich, T. and Thompson, L. M. (2009). Animal models of polyglutamine diseases and therapeutic approaches. J Biol Chem 284, 7431-5.
  • Atcha, FA, Syed, A, Wu, B, Hoverter, N, Yokoyama, N, Ting, J. T., Munguia, J. E., Mangalam, H. J., Marsh*, J. L., and Waterman, M. L.* (2007) A unique DNA binding domain converts T-cell factors into strong Wnt effectors. Mol Cell Biol 27, 8352-63
  • Theisen, H., Syed, A., Nguyen, BT., Lukacsovich, T., Purcell, J., Srivastava, GP., Iron, D., Gaudenz, K., Nie, Q., Wan, FYM., Waterman, ML., and Marsh, JL. (2007) Wingless Directly Represses DPP Morphogen Expression Via an Armadillo/TCF/Brinker Complex. PloS ONE 2(1): e142. doi:10.1371/journal.pone.0000142
  • Mizutani CM, Nie Q, Wan FY, Zhang YT, Vilmos P, Sousa-Neves R, Bier E, Marsh, J.L. , Lander AD. (2005) Formation of the BMP activity gradient in the Drosophila embryo. Developmental Cell 8,915-24.
  • Marsh, J. L. and Thompson, L. M. (2006). Drosophila in the study of neurodegenerative disease. Neuron 52, 169-78.
  • Agrawal, N., Pallos, J., Slepko, N.,Apostol, B. L., Bodai, L., Chang, L., Chiang, A., Thompson, L. M., and Marsh, J. L. (2005) Identification of combinatorial drug regimens for treatment of Huntington’s disease using Drosophila. PNAS. 102, 3777-81
  • Vilmos, V., Sousa-Neves, R., Lukacsovich, T. and Marsh, J.L. (2005) Crossveinless defines a new family of Twisted Gastrulation-like modulators of BMP signaling. EMBO reports 6, 262-267.

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