Harry T. Orr, Ph.D., Institute of Human Genetics at the University of Minnesota

Director,
Institute of Human Genetics
Tulloch Professor of Genetics,
Department of Laboratory Medicine and Pathology
515 Delaware Street, S.E.
Mayo Mail Code 206
5-211 Moos Tower
Minneapolis, MN 55455
Phone: (612) 625-3647
Fax: (612) 626-7031
e-mail: orrxx002@umn.edu

Research Interests

Our group works at unraveling genes that encode proteins critical for proper neuronal function. The primary approach is to study genes that have a role in neurodegeneration. We study the molecular basis of spinocerebellar ataxia type 1 (SCA1). SCA1 is a dominantly inherited neurodegenerative disease caused by an expanded glutamine tract in ataxin-1. How does a mutant glutamine tract in ataxin-1 lead to neuronal dysfunction and cell loss? To answer this, we feel it is important to understand the normal function of ataxin-1 and how a mutant polyglutamine tract alters its function. Using transgenic mice, we found that mutant ataxin-1 must enter the nucleus in affected neurons to cause disease (Klement, 1998). Several strategies have been used to show that in the presence of mutant ataxin-1 gene expression by Purkinje cells is altered (Serra, 2004). What's more, ataxin-1 has RNA-binding activity (Yue, 2001), and is able to shuttle between the nucleus and cytoplasm. We found that ataxin-1 is normally phosphorylated at serine 776 (S776) that is critical for ataxin-1 induced degeneration (Emamian, 2003). Recently, we generated a conditional mouse model of SCA1 in which the expression of mutant ataxin-1 can be turned on and off at will (Zu, 2004). These mice are proving to be a valuable resource for examining the process of disease as well as pathways that are important for neuronal repair.

Selected/Recent Publications

• Klement, I.A., Skinner, P.J., Kaytor, M.D., Yi, H., Hersch, S.M., Clark, H.B., Zoghbi, H.Y., and Orr, H.T. (1998) Ataxin-1 nuclear localization and aggregation: Role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41-53.
• Yue, S., Serra, H., Zoghbi, H.Y., and Orr, H.T. (2001) The SCA1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract. Hum. Mol. Genet. 10: 25-30.
• Emamian, E.S., Kaytor, M.D., Duvick, L.A., Zu, T., Tousey, S.K., Zoghbi, H.Y., Clark, H.B., and Orr, H.T. (2003) Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38: 375-387.
• Riley, B.E., Xu, Y., Zoghbi, H.Y., and Orr. H.T. (2004) The polyglutamine repeat protein ataxin-1 and its effects on the UbL-UBA protein, A1Up. J. Biol. Chem. 279: 42290-42301.
• Serra, H.G., Byam, C.E., Lande, J.D., Tousey, S.K., Zoghbi, H.Y., and Orr, H.T. (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13: 2535-2543.
• Zu, T, Duvick, L.A., Kaytor, M.D., Berlinger, M., Zoghbi, H.Y., Clark, H.B. and Orr, H.T. (2004) Recovery from polyglutamine-Induced neurodegeneration in conditional SCA1 transgenic mice. J. Neurosci . 24: 8853-8861.
• Riley, B.E., Zoghbi, H.Y., and Orr, H.T. (2005) SUMOylation of the polyglutamine protein, ataxin-1 is dependent ona functional nuclear localization signal. J. Biol. Chem. 280, 21942-21948.