Harry T. Orr, Ph.D.

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.