Harry T. Orr, Ph.D.

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

E-MAIL: [email protected]

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.)

  • Wozniak EAL, Chen Z, Paul S, Yang P, Figueroa KP, Friedrich J, Tschumperlin T, Berken M, Ingram M, Henzler C, Pulst SM, Orr HT. Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice. Cell Rep. 2021 Oct 12;37(2):109831.
  • Cendelin J, Cvetanovic M, Gandelman M, Hirai H, Orr HT, Pulst SM, Strupp M, Tichanek F, Tuma J, Manto M. Consensus paper: Strengths and weaknesses of animal models of spinocerebellar ataxias and their clinical implications. Cerebellum. 2021 Aug 10. doi: 10.1007/s12311-021-01311-1.
  • Lee WS, Lavery L, Rousseaux MWC, Rutledge EB, Jang Y, Wan YW, Wu SR, Kim W, Al-Ramahi I, Rath S, Adamski CJ, Bondar VV, Tewari A, Soleimani S, Mota S, Yalamanchili HK, Orr HT, Liu Z, Botas J, Zoghbi HY. Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1. EMBO J. 2021 Apr 1;40(7):e106106.
  • Nitschke L, Coffin SL, Xhako E, El-Najjar DB, Orengo JP, Alcala E, Dai Y, Wan YW, Liu Z, Orr HT, Zoghbi HY. Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1. JCI Insight. 2021 Feb 8;6(3):e144955.
  • O'Callaghan B, Hofstra B, Handler HP, Kordasiewicz HB, Cole T, Duvick L, Friedrich J, Rainwater O, Yang P, Benneyworth M, Nichols-Meade T, Heal W, Ter Haar R, Henzler C, Orr HT. Antisense oligonucleotide therapeutic approach for suppression of ataxin-1 expression: A safety assessment. Mol Ther Nucleic Acids. 2020 Jul 25;21:1006-1016.
  • Chao OY, de Velasco EMF, Pathak SS, Maitra S, Zhang H, Duvick L, Wickman K, Orr HT, Hirai H, Yang YM. Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism. Neuropsychopharmacology. 2020;45(7):1159-1170.
  • Friedrich J, Kordasiewicz HB, O'Callaghan B, Handler HP, Wagener C, Duvick L, Swayze EE, Rainwater O, Hofstra B, Benneyworth M, Nichols-Meade T, Yang P, Chen Z, Ortiz JP, Clark HB, Öz G, Larson S, Zoghbi HY, Henzler C, Orr HT. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight. 2018 Nov 2;3(21):e123193.
  • Pérez Ortiz JM, Mollema N, Toker N, Adamski CJ, O'Callaghan B, Duvick L, Friedrich J, Walters MA, Strasser J, Hawkinson JE, Zoghbi HY, Henzler C, Orr HT, Lagalwar S. Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiol Dis. 2018 Aug;116:93-105.
  • Rousseaux MWC, Tschumperlin T, Lu HC, Lackey EP, Bondar VV, Wan YW, Tan Q, Adamski CJ, Friedrich J, Twaroski K, Chen W, Tolar J, Henzler C, Sharma A, Bajić A, Lin T, Duvick L, Liu Z, Sillitoe RV, Zoghbi HY, Orr HT. ATXN1-CIC complex Is the primary driver of cerebellar pathology in spinocerebellar ataxia type 1 through a gain-of-function mechanism.  Neuron. 2018 Mar 21;97(6):1235-1243.
  • Orengo JP, van der Heijden ME, Hao S, Tang J, Orr HT, Zoghbi HY.  Motor neuron degeneration correlates with respiratory dysfunction in SCA1. Dis Model Mech. 2018 Feb 26;11(2):dmm032623.
  • Pérez Ortiz JM, Orr HT. Spinocerebellar Ataxia Type 1: Molecular Mechanisms of  Neurodegeneration and Preclinical Studies.  Adv Exp Med Biol. 2018;1049:135-145.
  • Paulson HL, Shakkottai VG, Clark HB, Orr HT. Polyglutamine spinocerebellar ataxias - from genes to potential treatments. Nat Rev Neurosci. 2017;18(10):613-626.
  • Lu HC, Tan Q, Rousseaux MW, Wang W, Kim JY, Richman R, Wan YW, Yeh SY, Patel JM, Liu X, Lin T, Lee Y, Fryer JD, Han J, Chahrour M, Finnell RH, Lei Y, Zurita-Jimenez ME, Ahimaz P, Anyane-Yeboa K, Van Maldergem L, Lehalle D, Jean-Marcais N, Mosca-Boidron AL, Thevenon J, Cousin MA, Bro DE, Lanpher BC, Klee EW, Alexander N, Bainbridge MN, Orr HT, Sillitoe RV, Ljungberg MC, Liu Z, Schaaf CP, Zoghbi HY. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017;49(4):527-536.
  • Liu CJ, Williams KE, Orr HT, Akkin T. Visualizing and mapping the cerebellum with serial optical coherence scanner. Neurophotonics. 2017 Jan;4(1):011006.
  • Tan Q, Yalamanchili HK, Park J, De Maio A, Lu HC, Wan YW, White JJ, Bondar VV, Sayegh LS, Liu X, Gao Y, Sillitoe RV, Orr HT, Liu Z, Zoghbi HY. Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet. 2016;25(23):5083-5093.
  • Rubinsztein DC, Orr HT. Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: There may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. Bioessays. 2016;38:977-980.
  • 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;89(6):1194-207.
  • Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, Lu JV, Nelson RW, Fife BT, Orr HT, Anderson MS, Hogquist KA, Jenkins MK. Polyclonal CD4+ T cell tolerance is established by distinct mechanisms, according to self-peptide expression patterns. Nat Immunol. 2016;17:187-95.
  • 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;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;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;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;289C:289-299.

Current Graduate Students:

Hillary Handler (Neuroscience, University of Minnesota).

Carrie Sheeler (Neuroscience, University of Minnesota).

Alyssa Soles (Neuroscience, University of Minnesota).

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).

Picture of Harry Orr