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[P3–144]: DISTINCT PATTERNS OF H2A.X PHOSPHORYLATION IN NEURONS: POTENTIAL ROLES IN HEALTH AND NEURODEGENERATIVE DISEASE
Author(s) -
Evans Mark D.,
Mucke Lennart
Publication year - 2017
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.2017.06.1355
Subject(s) - chromatin , dna damage , histone , biology , neurodegeneration , dna repair , microbiology and biotechnology , chromatin remodeling , phosphorylation , nucleus , epigenetics , cell nucleus , dna , genetics , gene , medicine , disease , pathology
Background:Genomic integrity is crucial to neuronal function, but becomes severely disrupted in neurodegenerative diseases. Central to maintaining genomic integrity is the DNA damage response, which acts to recruit proteins necessary for the repair of damaged DNA. Phosphorylation of histone H2A.X at serine 139 (gH2A.X), an early event in the DNA damage response, is required for the retention of multiple repair factors at DNA double-strand breaks (DSBs), including 53BP1. However, gH2A.X also occurs at sites of DNA single-strand breaks and chromatin remodeling, and can be induced during cellular stress and apoptosis. Thus, gH2A.X appears to play a role in the cellular response to a variety of insults, including DSBs. In neurons, gH2A.X levels are elevated by increased circuit activity, but the mechanisms underlying this response and its function(s) remain unclear. Methods:We analyzed gH2A.X and 53BP1 immunoreactivity at baseline and after neuronal activity manipulations in primary neuronal cultures and in brain sections from wildtype and human amyloid precursor protein (hAPP) transgenic mice. Results: We show that neuronal gH2A.X immunoreactivity exists in two major patterns: (1) focal, likely representing DSBs, especially when colocalized with 53BP1, and (2) nucleus-wide, which is unlikely to represent DSBs. Pharmacological stimulation of primary neuronal cultures led to striking activity-dependent increases in nucleus-wide gH2A.X, but not 53BP1. This response was reversed 6 h after cultures were returned to baseline conditions. Pharmacologically induced epilepsy in wildtype mice also increased nucleus-wide gH2A.X in neuronal populations throughout the hippocampus in vivo. Conclusions: These data suggest that, independent of DSBs, neuronal gH2A.X formation is involved in activity-induced chromatin remodeling and, possibly, changes in gene expression. Ongoing investigations use mass spectrometry-based approaches to assess the abundance of multiple DNA repair factors in postmortem tissues from patients with Alzheimer’s disease and controls, as well as genetic modulations of such factors in experimental models.