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Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles.
Handler, Hillary P; Duvick, Lisa; Mitchell, Jason S; Cvetanovic, Marija; Reighard, Molly; Soles, Alyssa; Mather, Kathleen B; Rainwater, Orion; Serres, Shannah; Nichols-Meade, Tessa; Coffin, Stephanie L; You, Yun; Ruis, Brian L; O'Callaghan, Brennon; Henzler, Christine; Zoghbi, Huda Y; Orr, Harry T.
Affiliation
  • Handler HP; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • Duvick L; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Mitchell JS; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Cvetanovic M; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • Reighard M; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Soles A; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • Mather KB; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • Rainwater O; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Serres S; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Nichols-Meade T; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
  • Coffin SL; Program in Genetics & Genomics and Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
  • You Y; Mouse Genetics Laboratory, University of Minnesota, Minneapolis, MN 55455, USA.
  • Ruis BL; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
  • O'Callaghan B; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  • Henzler C; RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  • Zoghbi HY; Departments of Molecular and Human Genetics, Pediatrics, and Howard Hughes Medical Institute, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
  • Orr HT; Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: orrxx002@umn.edu.
Neuron ; 111(4): 493-507.e6, 2023 02 15.
Article in En | MEDLINE | ID: mdl-36577403
ABSTRACT
Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates that proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spinocerebellar Ataxias / Transcriptome / Ataxin-1 Limits: Animals Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Document type: Article Affiliation country: Estados Unidos
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spinocerebellar Ataxias / Transcriptome / Ataxin-1 Limits: Animals Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2023 Document type: Article Affiliation country: Estados Unidos