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Genomes and Genes | H T OrrSummaryAffiliation: University of Minnesota Country: USA Publications
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Nuclear ataxiasHarry T Orr
Institute of Translational Neuroscience, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA
Cold Spring Harb Perspect Biol 2:a000786. 2010..Ataxias, lethal neurodegenerative diseases that are distinguished by a progressive loss of motor coordination, stem from disruption of nuclear function...- SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776Lisa Duvick
Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Neuron 67:929-35. 2010..Ser776 is critical for the pathway to neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death... 
SCA1 molecular genetics: a history of a 13 year collaboration against glutaminesH T Orr
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, Cell Biology and Development, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA
Hum Mol Genet 10:2307-11. 2001..Finally, several cellular pathways have been identified which are able to impinge on the SCA1 disease process. The characterization of these pathways and their role in SCA1 will guide research over the next several years...- The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1 (SCA1)H T Orr
Department of Genetics, University of Minnesota, Minneapolis, Minnesota, 55455, USA
Neurobiol Dis 7:129-34. 2000..This review summarizes these findings and places them in a context of potential future research directions... - Into the depths of ataxiaHarry T Orr
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
J Clin Invest 113:505-7. 2004..Thus, how a disruption in cerebellar cortex might lead to ataxia is of considerable interest. A report in this issue of the JCI links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei... - RNA gains a new function: a mediator of neurodegenerationHarry T Orr
Institute of Human Genetics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Trends Neurosci 27:233-4. 2004..demonstrated, in Drosophila, that FMR1 premutation RNA causes neurodegeneration. These data show RNA can induce neurodegeneration and provide strong evidence that FMR1 RNA mediates the neurodegeneration in human premutation carriers... - Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic miceI A Klement
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Cell 95:41-53. 1998..However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice... - Spinocerebellar ataxia type 1--modeling the pathogenesis of a polyglutamine neurodegenerative disorder in transgenic miceH B Clark
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis 55455, USA
J Neuropathol Exp Neurol 59:265-70. 2000..Present and future generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related disorders... - Qs in the nucleusH T Orr
Institute of Human Genetics, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA
Neuron 31:875-6. 2001..2001) provide insight into the cell specificity of pathology for a polyglutamine disease by relating SCA7-induced retinal degeneration to a disruption of the photoreceptor-specific transcription factor CRX... - Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic miceP J Skinner
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA
Am J Pathol 159:905-13. 2001.... - Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7M D Kaytor
Institute of Human Genetics, University of Minnesota, Minneapolis 55455, USA
Hum Mol Genet 8:1657-64. 1999..Mutation of this NLS prevented protein from entering the nucleus. Thus, expanded ataxin-7 may carry out its pathogenic effects in the nucleus by altering a matrix-associated nuclear structure and/or by disrupting nucleolar function... - Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic miceEffat S Emamian
Department of Laboratory Medicine and Pathology, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA
Neuron 38:375-87. 2003..We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis... - The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tractS Yue
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, Mayo Mail Code 206, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Hum Mol Genet 10:25-30. 2001..These observations suggest that ataxin-1 plays a role in RNA metabolism and that the expansion of the polyglutamine tract may alter this function... - Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structuresP J Skinner
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Nature 389:971-4. 1997..We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain... - Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterationsH B Clark
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Neurosci 17:7385-95. 1997.... - Identification and characterization of an ataxin-1-interacting protein: A1Up, a ubiquitin-like nuclear proteinJ D Davidson
Department of Genetics, Cell Biology and Development, Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA
Hum Mol Genet 9:2305-12. 2000..In addition, these data support the concept that ataxin-1 may function in the formation and regulation of multimeric protein complexes within the nucleus... - Identification of a self-association region within the SCA1 gene product, ataxin-1E N Burright
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Hum Mol Genet 6:513-8. 1997..These results, while identifying an ataxin-1 self-interaction region, fail to support a proposed model of polar-zipper mediated multimerization involving the ataxin-1 polyglutamine tract... - Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic miceTao Zu
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Neurosci 24:8853-61. 2004..Of note, even at a late stage of disease, Purkinje cells retain at least some ability to repair the damage caused by mutant ataxin-1... - RNA targets of the fragile X proteinM D Kaytor
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Box 206, University of Minnesota Health Center, Minneapolis, MN 55455, USA
Cell 107:555-7. 2001..They provide further support for the importance of local protein synthesis within a neuron as a determinant of proper synaptogenesis and the development of cognitive abilities... - Mouse models of human CAG repeat disordersE N Burright
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Brain Pathol 7:965-77. 1997.... - Susceptibility to cell death induced by mutant SV40 T-antigen correlates with Purkinje neuron functional developmentR M Feddersen
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Mol Cell Neurosci 9:42-62. 1997..These data indicate that Purkinje cell death susceptibility varies with developmental stage... - SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeatE N Burright
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Cell 82:937-48. 1995..These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions... - Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic micePamela J Skinner
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA
Neuromolecular Med 1:33-42. 2002..Thus, these data suggest that this region of ataxin-1 has a role in disease progression. Furthermore, these results provide evidence that ataxin-1-induced disease initiation and disease progression involve distinct molecular events... - Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1H T Orr
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455
Nat Genet 4:221-6. 1993..We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat... - Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic miceHeliane G Serra
Department of Laboratory Medicine and Pathology, University of Minnesota, Mayo Mail Code 206, Minneapolis, Minnesota 55455, USA
Hum Mol Genet 13:2535-43. 2004..Interestingly, five of the genes in this group form a biological cohort centered on glutamate signaling pathways in Purkinje cells... - RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 miceHeliane G Serra
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA
Cell 127:697-708. 2006..These studies indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult... - Trinucleotide repeat disordersHarry T Orr
Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA
Annu Rev Neurosci 30:575-621. 2007..It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets... - Hsp70/Hsc70 regulates the effect phosphorylation has on stabilizing ataxin-1Nathan D Jorgensen
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Neurochem 102:2040-8. 2007..However, Akt targeted to the cytoplasm failed to destabilize ATXN1 if Hsp70/Hsc70 was present. Thus, Hsp70/Hsc70 can regulate ATXN1 levels in concert with phosphorylation of ATXN1 at S776... - Fragile X tremor/ataxia syndrome: blame the messenger!Maurice S Swanson
Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Cancer Genetics Research Complex, 1376 Mowry Road, Gainesville, FL 32610 3610, USA
Neuron 55:535-7. 2007..Two reports in this issue of Neuron (Jin et al. and Sofola et al.) present data indicating a disease mechanism involving disruption of RNA-binding protein function... - Unstable nucleotide repeat minireview series: a molecular biography of unstable repeat disordersHarry T Orr
Institute of Human Genetics and the Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Biol Chem 284:7405. 2009..This collection of minireviews examines several of these unstable repeats, focusing on those where there is considerable molecular information on how the mutation alters function... - Emerging pathogenic pathways in the spinocerebellar ataxiasKerri M Carlson
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, United States
Curr Opin Genet Dev 19:247-53. 2009..Understanding how these genes cause disease will allow a deeper understanding of the cerebellum in particular as well as neurodegenerative disease in general... - Phosphorylation of ATXN1 at Ser776 in the cerebellumNathan D Jorgensen
Institute of Human Genetics, University of Minnesota, Minneapolis, 55455, USA
J Neurochem 110:675-86. 2009..These results argue against Akt as the in vivo kinase that phosphorylates S776 of ATXN1 and suggest that cyclic AMP-dependent protein kinase is the active ATXN1-S776 kinase in the cerebellum... - Noninvasive detection of presymptomatic and progressive neurodegeneration in a mouse model of spinocerebellar ataxia type 1GULIN OZ
Center for Magnetic Resonance Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Neurosci 30:3831-8. 2010..These data demonstrate that presymptomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS... - SUMOylation of the polyglutamine repeat protein, ataxin-1, is dependent on a functional nuclear localization signalBrigit E Riley
Department of Biochemistry, Molecular Biology, Biophysics, Institute of Human Genetics, The University of Minnesota, Minneapolis, MN 55455, USA
J Biol Chem 280:21942-8. 2005..Lys(16), Lys(194) preceding the polyglutamine tract, Lys(610)/Lys(697) in the C-terminal ataxin high mobility group domain, and Lys(746) all contribute to ataxin-1 SUMOylation... - Identification of a novel phosphorylation site in ataxin-1Cynthia A Vierra-Green
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6 155 Jackson Hall, 321 Church St Minneapolis, MN 55455, USA
Biochim Biophys Acta 1744:11-8. 2005..Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and mutational analysis demonstrated a novel phosphorylation site at serine 239 of ataxin-1... - Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzleBrigit E Riley
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
Genes Dev 20:2183-92. 2006..This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription... - Antisense RNA sequences modulating the ataxin-1 message: molecular model of gene therapy for spinocerebellar ataxia type 1, a dominant-acting unstable trinucleotide repeat diseaseYouxin Gao
Institute of Human Genetics, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Cell Transplant 17:723-34. 2008..We conclude that antisense RNAs were effective in reducing or modifying ataxin-1 messages in transfected cells, and may be an effective genetic strategy for therapy of SCA1 and similar dominant-acting neurological disorders... - The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1UpBrigit E Riley
Department of Biochemistry, Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Biol Chem 279:42290-301. 2004..Interestingly, the interaction between A1Up and mutant ataxin-1-(82Q) increased the half-life of A1Up, whereas nonpathogenic wild-type ataxin-1-(30Q) or ataxin-1-(82Q)-A776 did not... - Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxiaL P Ranum
Department of Neurology, University of Minnesota, Minneapolis, USA
Am J Hum Genet 57:603-8. 1995..838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively... - Targeted deletion of a single Sca8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficitsYungui He
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Neurosci 26:9975-82. 2006.... - Microarrays and polyglutamine disorders: reports from the Hereditary Disease Array GroupHarry T Orr
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA
Hum Mol Genet 11:1909-10. 2002 - Isolation, characterization and in vivo analysis of the murine calbindin-D28K upstream regulatory regionO Pavlou
Department of Genetics and Cell Biology, University of Minnesota, Minneapolis 55455, USA
Brain Res Mol Brain Res 36:268-79. 1996..0 kb of calbindin upstream sequence includes the regulatory elements dictating a portion of cell-specificity in the CNS of transgenic mice, albeit lacking regions that allow expression independently of chromosomal effects... - cDNA cloning and characterization of three genes uniquely expressed in cerebellum by Purkinje neuronsD T Nordquist
Institute of Human Genetics, University of Minnesota, Minneapolis 55455
J Neurosci 8:4780-9. 1988..To define potential correlations between the PCD clones and mutations in the mouse genome known to affect Purkinje cells, clones PCD5, PCD6, and PCD29 were localized to mouse chromosomes 8, 6, and 4, respectively... - A cell-based screen for modulators of ataxin-1 phosphorylationMichael D Kaytor
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
Hum Mol Genet 14:1095-105. 2005..These results provide new molecular tools to aid in elucidating the biological role of ataxin-1 phosphorylation and perhaps provide potential leads toward the development of a therapy for SCA1... - Overexpression of CREB reduces CRE-mediated transcription: behavioral and cellular analyses in transgenic miceChristopher R Brodie
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA
Mol Cell Neurosci 25:602-11. 2004..Furthermore, we conclude that CRE-mediated transcription may be linked to only a subset of cerebellum-mediated motor behaviors and may not be universally required for long-lasting synaptic potentiation... - The GSK3 beta signaling cascade and neurodegenerative diseaseMichael D Kaytor
Department of Laboratory Medicine and Pathology and Institute of Human Genetics, University of Minnesota, Mayo Mail Code 206, Minneapolis, Minnesota 55455, USA
Curr Opin Neurobiol 12:275-8. 2002..How GSK3 acts in this regard is still open to debate, but it may involve both extracellular and nuclear apoptotic activities... - miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesisYoontae Lee
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
Nat Neurosci 11:1137-9. 2008..We provide a new candidate mechanism for modulating the pathogenesis of neurodegenerative diseases sensitive to protein dosage... - Mapmodulin/leucine-rich acidic nuclear protein binds the light chain of microtubule-associated protein 1B and modulates neuritogenesisPuneet Opal
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA
J Biol Chem 278:34691-9. 2003..LANP thus could play a key role in neuronal development and/or neurodegeneration by its interactions with microtubule associated proteins... - RNA association and nucleocytoplasmic shuttling by ataxin-1Stuart Irwin
McMaster University, HSC 4H45, Department of Biochemistry, Hamilton, Ontario, L8N 3Z5, Canada
J Cell Sci 118:233-42. 2005..These results suggest that the normal role of ataxin-1 may be in RNA processing, perhaps nuclear RNA export. Thus, nuclear retention of mutant ataxin-1 may be an important toxic gain of function in SCA1 disease... - Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1Hung Kai Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Cell 113:457-68. 2003..Our finding that phosphatidylinositol 3-kinase/Akt signaling and 14-3-3 cooperate to modulate the neurotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and identifies potential targets for therapeutic intervention... - A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegenerationKei Watase
Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
Neuron 34:905-19. 2002..It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity... - Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1Janghoo Lim
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
Nature 452:713-8. 2008..This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases... - The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7Jennifer R Gatchel
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
Proc Natl Acad Sci U S A 105:1291-6. 2008..These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis... - Regional differences of somatic CAG repeat instability do not account for selective neuronal vulnerability in a knock-in mouse model of SCA1Kei Watase
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA
Hum Mol Genet 12:2789-95. 2003..The finding that somatic instability is most pronounced in the striatum of various knock-in models of polyglutamine diseases highlights the role of trans-acting tissue- or cell-specific factors in mediating the instability... 
Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse modelKei Watase
21st Century COE program on Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo, Japan
PLoS Med 4:e182. 2007....- ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathologyYung C Lam
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
Cell 127:1335-47. 2006..These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions... - RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxiaHaibin Xia
Program in Gene Therapy, University of Iowa, Iowa City, Iowa, USA
Nat Med 10:816-20. 2004..Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease... - Neurodegenerative disease: cut to the chaseLisa M Ellerby
Nature 442:641-2. 2006 - The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteinsHiroshi Tsuda
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
Cell 122:633-44. 2005..Interestingly, loss of Gfi-1 mimics SCA1 phenotypes in Purkinje cells. These results indicate that the Atx-1/Gfi-1 interaction contributes to the selective Purkinje cell degeneration in SCA1... - Neurodegenerative disease: neuron protection agencyHarry T Orr
Nature 431:747-8. 2004 - Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexesAaron B Bowman
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Nat Genet 39:373-9. 2007.... - Generation and characterization of LANP/pp32 null micePuneet Opal
Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
Mol Cell Biol 24:3140-9. 2004..Overall our results point to a functional redundancy of LANP's function, most likely provided by its closely related family members...
Research Grants
- Modulation of ataxin-1 phosphorylationHarry Orr; Fiscal Year: 2006..Lead compounds that have been validated will be used to begin preclinical testing using a mouse model of SCA1. ..
- MOLECULAR GENETICS OF THE SCA1 LOCUSHarry Orr; Fiscal Year: 2007..Understanding the importance of these factors for SCA1 pathogenesis should provide insights for polyglutamine diseases in general. ..