Harry T. Orr, Ph.D.

Professor, Department of Laboratory Medicine and Pathology Tulloch Professor of Genetics Director, Institute for Translational Neuroscience

E-MAIL: orrxx002@umn.edu

Research Interests:

Mechanisms underlying the development and aging of neurons in the cerebellum. Discovered that an expanded CAG trinucleotide repeat causes spinocerebellar ataxia type 1 (SCA1). Established the first transgenic mouse model of a polyglutamine neurodegenerative disease and using it to elucidate SCA1 pathogenesis. Demonstrated the importance of nuclear localization of the mutant protein for pathogenesis and demonstrated that sequences beyond the CAG expansion are critical for selectivity of neuronal susceptibility.

Selected Publications:

(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)

Ingram M, Wozniak EA, Duvick L, Yang R, Bergmann P, Carson R, O'Callaghan B, Zoghbi HY, Henzler C, Orr HT. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron. 2016 Mar 16;89(6):1194-207.

Malhotra, D., Linehan, J.L., Dileepan, T., Lee, Y.-J., Nelson, R.W., Fife, B.T., Orr, H.T., Anderson, M.S., Hogquist, K.A., and Jenkins, M.K. (2016) Polyclonal CD4+ T cell tolerance is established by distinct mechanisms, according to self-peptide expression patterns. Nature Immunol., in press.

Dell'Orco JM, Wasserman AH, Chopra R, Ingram MA, Hu YS, Singh V, Wulff H, Opal P, Orr HT, Shakkottai VG. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability. J Neurosci. 2015 Aug 12;35(32):11292-307.

Lasagna-Reeves CA, Rousseaux MW, Guerrero-Muñoz MJ, Park J, Jafar-Nejad P, Richman R, Lu N, Sengupta U, Litvinchuk A, Orr HT, Kayed R, Zoghbi HY. A native interactor scaffolds and stabilizes toxic ATAXIN-1 oligomers in SCA1. Elife. 2015 May 19;4.

Gennarino VA, Singh RK, White JJ, De Maio A, Han K, Kim JY, Jafar-Nejad P, di Ronza A, Kang H, Sayegh LS, Cooper TA, Orr HT, Sillitoe RV, Zoghbi HY. Pumilio1 Haploinsufficiency Leads to SCA1-like Neurodegeneration by Increasing Wild-Type Ataxin1 Levels. Cell. 2015 Mar 12;160(6):1087-98.

Öz G, Kittelson E, Demirgöz D, Rainwater O, Eberly LE, Orr HT, Clark HB. Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology. Neurobiol Dis. 2015 Feb;74:158-66.

Cvetanovic M, Ingram M, Orr H, Opal P. Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience. 2015 Jan 14;289C:289-299.

Lagalwar S, Orr HT. Regulation of ataxin-1 phosphorylation and its impact on biology. Methods Mol Biol. 2013;1010:201-9.

Lai, S., O'Callaghan, B., Zoghbi, H.Y., and Orr, H.T. (2011) 14-3-3 binding to ataxin-1(ATXN1) regulates its dephosphorylation at S776 and transport to the nucleus. J. Biol. Chem. 286: 34606-34616. PMID: 21835928

Barnes, J., Ebner, B.A., Duvick, L.A., Gao, W., Chen, G., Orr, H.T., and Ebner, T.J. (2011) Abnormalities in the climbing fiber-purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J. Neuroscience 31:12778-12789. PMID: 21900557

Duvick, L., Barnes,J., Ebner, B., Agrawal, S., Andresen, M., Lim, J., Giesler, G.J., Zoghbi, H.Y., and Orr. H.T. (2010) SCA1-like disease in mice expressing wild type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 67: 929-935. PMID: 20869591

Öz, G., Nelson, C.D., Koski, D.M., Henry, P.-G., Marjanska, M., Deelchand, D.K., Shanley, R., Eberly, L.E., Orr, H.T., Clark, H.B. (2010) Noninvasive detection of pre-symptomatic and progressive neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J. Neurosci. 30: 3831-3838. PMID: 2846771

Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A.B., Richman, R., Hill, D.E., Orr, H.T. and Zoghbi, H.Y. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1, Nature 452: 713-719.

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.

Serra, H.G., Duvick, L., Zu, T., Carlson, K., Stevens, S., Jorgensen, N., Lysholm, A., Burright, E., Zoghbi, H.Y., Clark, H.B., Andresen, J.M., and Orr, H.T. (2006) ROR_-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127: 697-708.

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.

Emamian, E.S. , Kaytor, M.D., Duvick, L.A., Zu, T., Susan K. 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.

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.

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.

Burright, E.N., Clark, H.B., Servadio, A., Matilla, T., Feddersen, R.M., Yunis, W.S., Duvick, L.A., Zoghbi, H.Y., and Orr, H.T.  (1995)  SCA1 transgenic mice:  a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.  Cell  82:937-948.

Former Graduate Students:

Judit Perez-Ortiz (Ph.D. 2016, Neuroscience, University of Minnesota).

Emily Wozniak (Leathley) (Ph.D. 2016, Neuroscience, University of Minnesota)

Justin Barnes (Ph.D. 2011, Neuroscience, University of Minnesota).

Nathan Jorgensen (Ph.D. 2007, Neuroscience, University of Minnesota).

Harry Orr