title: The role of ATM and DNA damage in neurons: upstream and downstream connections.
abstract: ATM (ataxia-telangiectasia mutated) is a large protein kinase whose best-known function is as a participant in the process of DNA damage repair, specifically lesions that result in double strand breaks. In the cells of the nervous system, however, the symptoms of children with ataxia-telangiectasia and the phenotypes of mice with engineered mutations in their ATM gene argue for a broader range of protein functions. ATM is now appreciated to play a role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Finally, the decline of ATM levels with age suggest that late onset neurodegenerative diseases may owe part of their pathogenesis to deficits in ATM signaling. Evidence from the location of HDAC4 in the hippocampal pyramidal cells of the Alzheimer's disease brain supports this hypothesis. These multiple functions of the ATM protein are in keeping with the complex multi-system nature of the symptoms of ataxia-telangiectasia and encourage us to look beyond DNA damage for the full understanding of the disease and its consequences.
authors.affiliation: Division of Life Sciences, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. herrup@biology.rutgers.edu
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000375:Aging; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases; D006801:Humans; D009154:Mutation; D009420:Nervous System; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D012097:Repressor Proteins; D015398:Signal Transduction
chemical_list: D012097:Repressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: Alzheimer's disease; Ataxia-telangiectasia; DNA damage; Epigenetics; Glutamine