title: ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis.
abstract: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the gene ataxin-2 (ATXN2). ATXN2 intermediate-length CAG expansions were identified as a risk factor for amyotrophic lateral sclerosis (ALS). The ATXN2 CAG repeat is translated into polyglutamine, and SCA2 pathogenesis has been thought to derive from ATXN2 protein containing an expanded polyglutamine tract. However, recent evidence of bidirectional transcription at multiple CAG/CTG disease loci has led us to test whether additional mechanisms of pathogenesis may contribute to SCA2.
  
  
  
  In this work, using human postmortem tissue, various cell models, and animal models, we provide the first evidence that an antisense transcript at the SCA2 locus contributes to SCA2 pathogenesis.
  
  
  
  We demonstrate the expression of a transcript, containing the repeat as a CUG tract, derived from a gene (ATXN2-AS) directly antisense to ATXN2. ATXN2-AS transcripts with normal and expanded CUG repeats are expressed in human postmortem SCA2 brains, human SCA2 fibroblasts, induced SCA2 pluripotent stem cells, SCA2 neural stem cells, and lymphoblastoid lines containing an expanded ATXN2 allele associated with ALS. ATXN2-AS transcripts with a CUG repeat expansion are toxic in an SCA2 cell model and form RNA foci in SCA2 cerebellar Purkinje cells. Finally, we detected missplicing of amyloid beta precursor protein and N-methyl-D-aspartate receptor 1 in SCA2 brains, consistent with findings in other diseases characterized by RNA-mediated pathogenesis.
  
  
  
  These results suggest that ATXN2-AS has a role in SCA2 and possibly ALS pathogenesis, and may therefore provide a novel therapeutic target for these diseases. Ann Neurol 2016;80:600-615.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Pan P
authors.initials: PP
authors.lastname: Li
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.|Research and Neurology Services, Veterans Affairs Medical Center, Albany, NY.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Neurology, College of Medicine, and McKnight Brain Institute, University of Florida, Gainesville, FL.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Xia
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arbez
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, UT.
authors.forename: Sharan
authors.initials: S
authors.lastname: Paul
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Peng
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.|Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Research and Neurology Services, Veterans Affairs Medical Center, Albany, NY.|Department of Neurology and Pathology, Albany Medical College, Albany, NY.
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Koeppen
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.|Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, UT.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
authors.affiliation: Department of Neurology, College of Medicine, and McKnight Brain Institute, University of Florida, Gainesville, FL.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. drudnic1@jhmi.edu.|Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. drudnic1@jhmi.edu.
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000067698:Ataxin-2 / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D055815:Young Adult
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2