title: Neurons in Vulnerable Regions of the Alzheimer's Disease Brain Display Reduced ATM Signaling.
abstract: Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer's disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function-nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity-appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
authors.forename: Xuting
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University , Piscataway, New Jersey 08854.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, and Yunnan Province, Kunming Institute of Zoology , Kunming 650223, Yunnan, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology and The Alzheimer's Disease Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15213.
authors.forename: Julia
authors.initials: J
authors.lastname: Kofler
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Karl
authors.identifier: 0000-0001-7786-5844
authors.initials: K
authors.lastname: Herrup
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000201:enzymology; D004195:Disease Models, Animal; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D012097:Repressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: EZH2; HDAC4; ataxia-telangiectasia; cell cycle; neurodegeneration