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Sci Transl Med. 2014 Dec 24;6(268):268ra178. doi: 10.1126/scitranslmed.3010523.

Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease.

Author information

1
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.
2
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
3
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.
4
BioFocus, a Charles River company, Leiden 233CR, the Netherlands.
5
Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand.
6
Department of Biochemistry and Cellular and Molecular Biology, Knoxville, TN 37996, USA.
7
NIH Chemical Genomic Center, National Center for Advancing Translation Sciences, National Institutes of Health, Rockville, MD 20892, USA.
8
Galapagos, Leiden, the Netherlands.
9
Department of Pathology and Laboratory Medicine (Neurology), David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
10
CHDI Foundation/CHDI Management Inc., Los Angeles, CA 90045, USA.
11
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.

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.

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PMID:
25540325
DOI:
10.1126/scitranslmed.3010523
[Indexed for MEDLINE]

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