Open AccessNeuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1
Author(s) -
Wang David B.,
Kinoshita Chizuru,
Kinoshita Yoshito,
Sopher Bryce L.,
Uo Takuma,
Lee Rona J.,
Kim Joon Kyu,
Murphy Sean P.,
Dirk Keene C.,
Garden Gwenn A.,
Morrison Richard S.
Publication year - 2019
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12647
Subject(s) - gene knockdown , hdac1 , histone deacetylase , histone , microbiology and biotechnology , mfn2 , histone deacetylase 2 , chemistry , biology , cancer research , apoptosis , mitochondrial fusion , biochemistry , gene , mitochondrial dna
Histone deacetylases ( HDAC s) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC 2 is highly expressed in adult brain, and HDAC 2 levels are elevated in Alzheimer's disease ( AD ) brain. We previously reported that neuron‐specific splice isoforms of Endophilin‐B1 (Endo‐B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC 2 suppresses Endo‐B1 expression. HDAC 2 knockdown or knockout enhances expression of Endo‐B1. Conversely, HDAC 2 overexpression decreases Endo‐B1 expression. We also demonstrate that neurons exposed to beta‐amyloid increase HDAC 2 and reduce histone H3 acetylation while HDAC 2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase‐3 activation, and neuronal death. The protective effect of HDAC 2 knockdown was abrogated by Endo‐B1 sh RNA and in Endo‐B1‐null neurons, suggesting that HDAC 2‐induced neurotoxicity is mediated through suppression of Endo‐B1. HDAC 2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor ( MFF ), recapitulating the pattern of change observed in AD . HDAC 2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion ( MCAO /R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo‐B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC 2 represses Endo‐B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD .