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P4‐212: The loss of atm protein drives neuronal degeneration: A new insight into Alzheimer's disease pathogenesis
Author(s) -
Shen Xuting,
Chen Jianmin,
Kofler Julia,
Herrup Karl
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.08.040
Subject(s) - biology , histone , cell cycle , neuroscience , programmed cell death , microbiology and biotechnology , dna damage , cell , apoptosis , genetics , dna
Background: The ATM kinase is involved in the DNA damage response. Mutations in ATM lead to ataxia-telangiectasia (A-T), a progressive childhood movement disorder associated with a massive loss of cerebellar neurons. The death of these neurons occurs in association with their re-entrance into a cell cycle. During the DNA damage response ATM activates a cell cycle checkpoint; therefore, in the absence of ATM, the loss of neuronal cell cycle control is not unexpected. Neurons in Alzheimer’s disease also undergo a cell cycle related cell death and thus, despite their vastly different clinical nature, we asked whether neuronal deaths in AT and AD might be similar. Methods: Recently, the cellular roles of ATM have been expanded to include the correct cytoplasmic localization of histone deacetylase-4 (HDAC4) and stimulating the degradation of the histone methyltransferase, EZH2. In ATMdeficient neurons, therefore HDAC4 is found in the nucleus and the levels of histone methylation (specifically H3K27me3) are elevated. Paraffin sections from confirmed cases of AD, MCI and cognitively normal controls were immunostained for HDAC4, H3K27me3 and cell cycle proteins. Results:We used all three measures of reduced ATM activity to query the status of cells at risk for death in AD. We found strong correlations between AD stage and evidence for a cell autonomous loss of ATM activity. This relationship held true in three different brain regions where neurons are known to be lost in AD – hippocampus, frontal cortex and locus coeruleus. Cerebellar cortex showed no disease related changes in any measure. Double labeling of cells for two independent markers (e.g., cell cycle activity and nuclear HDAC4 localization) revealed a strong overlap in these measures of reduced ATM activity. Conclusions: ATM activity is responsible for the maintenance of neuronal health throughout the life span and the cell autonomous loss of its activity in nerve cells is a key driver of the neuronal death in Alzheimer’s disease. This unexpected relationship between a childhood movement disorder and a late-life dementing illness reveals a novel facet of the neurodegenerative process and suggests that enhancing ATM activity may have significant therapeutic potential in the treatment of AD.