title: Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease.
abstract: Age-related neurodegenerative disorders including Alzheimer's disease and Huntington's disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been demonstrated in Alzheimer's disease and in mouse models of other neurodegenerative diseases. We show that ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown protected from toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models. By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full-length human mHTT, we show that genetic reduction of Atm gene dosage by one copy ameliorated multiple behavioral deficits and partially improved neuropathology. Small-molecule ATM inhibitors reduced mHTT-induced death of rat striatal neurons and induced pluripotent stem cells derived from HD patients. Our study provides converging genetic and pharmacological evidence that reduction of ATM signaling could ameliorate mHTT toxicity in cellular and animal models of HD, suggesting that ATM may be a useful therapeutic target for HD.
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. UCLA Brain Research Institute, Los Angeles, CA 90095, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lu
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Mattis
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. UCLA Brain Research Institute, Los Angeles, CA 90095, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.affiliation: BioFocus, a Charles River company, Leiden 233CR, the Netherlands.
authors.forename: Nick
authors.initials: N
authors.lastname: van den Berg
authors.affiliation: BioFocus, a Charles River company, Leiden 233CR, the Netherlands.
authors.forename: Silvina A
authors.initials: SA
authors.lastname: Fratantoni
authors.affiliation: Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand.
authors.forename: Henry
authors.initials: H
authors.lastname: Waldvogel
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. UCLA Brain Research Institute, Los Angeles, CA 90095, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Greiner
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, Knoxville, TN 37996, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Osmand
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Elzein
authors.affiliation: NIH Chemical Genomic Center, National Center for Advancing Translation Sciences, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.affiliation: BioFocus, a Charles River company, Leiden 233CR, the Netherlands.
authors.forename: Sipke
authors.initials: S
authors.lastname: Dijkstra
authors.affiliation: Galapagos, Leiden, the Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: de Pril
authors.affiliation: Department of Pathology and Laboratory Medicine (Neurology), David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand.
authors.forename: Richard
authors.initials: R
authors.lastname: Faull
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, CA 90045, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Signer
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, CA 90045, USA.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: NIH Chemical Genomic Center, National Center for Advancing Translation Sciences, National Institutes of Health, Rockville, MD 20892, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: BioFocus, a Charles River company, Leiden 233CR, the Netherlands.
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, CA 90045, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. UCLA Brain Research Institute, Los Angeles, CA 90095, USA. xwyang@mednet.ucla.edu.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000378:metabolism; D018628:Gene Dosage; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008818:Mice, Neurologic Mutants; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D050505:Mutant Proteins / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011180:Postmortem Changes; D050486:Serotonin Plasma Membrane Transport Proteins / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013892:Thioxanthenes / Q000494:pharmacology
chemical_list: C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009025:Morpholines; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013892:Thioxanthenes; D064007:Ataxia Telangiectasia Mutated Proteins