Office: WLS, E204: 865-974-2279
Lab: WLS, A206: 865-974-4029
Ph.D. Microbial Immunology, University of Adelaide (Australia)
For several years the laboratory has been conducting research on various aspects of the early pathology of Huntington’s disease (HD). Although a relatively rare neurodegenerative disease, occurring in about 30,000 individuals in the United States, this is a devastating disorder caused by a mutation inherited in an autosomal dominant fashion, for which no cure and only limited treatments exist. Nevertheless, it is argued that the solution of one neurodegenerative disease caused by a single gene mutation would provide a model for the answers to more common complex neurodegenerative diseases, such as Alzheimer’s and Parkinson’s which both have multiple dominant genetic variants as well as more common sporadic forms.
The mutation that causes Huntington’s disease is caused by an expansion of a segment of the DNA that codes for repeats of the amino acid glutamine, giving rise to the concept that HD is a polyglutamine repeat disorder, particularly since these expanded polyglutamine regions of the protein coded by the expanded gene, ‘huntingtin,’ tend to form aggregates and these aggregates are used as markers of the disease at autopsy. Numerous animal models of HD have been developed which express various forms of the mutated protein.
Several years ago we developed novel methods for the detection of the earliest stages of aggregation in HD using in situ recruitment with synthetic polypeptides and accompanying methods for the detection of neuropil aggregates and intranuclear accumulations, using ultrasensitive immunohistochemical techniques. Subsequently, this laboratory has become an international reference site for studies of animal models of HD and the laboratory is currently involved in examining the neuroanatomical distribution of aggregates and a number of the known posttranslational modifications of the huntingtin protein in a wide range of both novel and established animal models of HD.
Wilburn, B., Rudnicki, D.D., Zhao, J., Weitz, T.M., Gu, X., Greiner, E., Sopher, B.L., La Spada, A.R., Osmand, A., Margolis, R.L., Sun, Y.I. and Yang, X.W. A novel antisense CAG repeat transcript at JPH3 locus mediating expanded polyglutamine protein toxicity in Huntington’s Disease-Like 2 (HDL2) mice. Neuron 70: 427-40, 2011.
Alexandru, A., Jagla, W., Graubner, S., Becker, A., Bäuscher, C., Kohlmann, S., Sedlmeier, R., Raber, K.A., Cynis, H., Rönicke, R., Reymann, K.G., Petrasch-Parwez, E., Hartlage-Rübsamen, E., Waniek, A., Rossner, S., Schilling, S., Osmand, A.P., Demuth, H.-U., Hörsten, S. Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroGlu-Aβ formation. J. Neuroscience, 31:12790-801, 2011.
Miller, J., Arrasate, M., Brooks, E., Peters-Libeu, C. Legleiter, J., Hatters, D., Curtis, J., Cheung, NeuroImage, 59:957-967, 2012K., Krishnan, P., Mitra, S., Widjaja, K., Shaby, B.A., Lotz, G.P., Newhouse, Y., Mitchell, E., Osmand, A., Gray, M., Thulasiramin, V., Saudou, F., Segal, M., Yang, X.W., Masliah, E., Thompson, L.M., Muchowski, P.J., Weisgraber, K.H. and Finkbeiner, S. Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nature Chem. Biol., 7:925-934, 2011.
Blockx, I., De Groof, G., Verhoye, M., Van Audekerke, J., Raber, K., Poot, D., Sijbers, J., Osmand, A.P., Von Hörsten, S., Van der Linden, A. Microstructural changes observed with DKI in a transgenic Huntington rat model: Evidence for abnormal neurodevelopment. NeuroImage, 59:957-967, 2012.
Yu, L., Petrasch-Parwez, E., Osmand, A.P., Redensek, A., Metzger, S., Clemens, L.E., Park, L., Howland, D., Tuunanen, P., Lehtimäki, K., Calaminus, C., Gu, X., Pichler, B.J., Yang, X.W., Riess, O., Nguyen, H.-P. A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J. Neurosci. 32:15426-38, 2012.
Tada, M., Coon, E.A., Osmand, A.P., Kirby, P.A., Martin, W., Wieler, M., Shiga, A., Shirasaki, H., Tada, M., Makifuchi, T., Yamada. M., Kakita. A., Nishizawa. M., Takahashi. H., Paulson, H.L. Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study. Acta Neuropathol. 124:749-60, 2012.
Reid S.J., Patassini, S., Handley, R.R., Rudiger, S.R., Mclaughlan, S.J., Osmand, A., Jacobsen, J.C., Morton, A.J., Weiss, A., Waldvogel, H.J., Macdonald, M.E., Gusella, J.F., Bawden, C.S, Faull, R.L.M., Snell, R.G. Further Molecular Characterisation of the OVT73 Transgenic Sheep Model of Huntington’s Disease Identifies Cortical Aggregates. J. Huntington’s Dis. 2:279-295, 2013.
Bhela. S., Mulik, S., Reddy, P.B.J, Richardson, R.L., Gimenez, F., Rajasagi, N.K., Veiga-Parga, T., Osmand, A.P., Rouse, B.T. Critical Role of MicroRNA-155 in Herpes Simplex Encephalitis. J. Immunol. 192: 2734-2743, 2014