Subcellular Distribution of HDAC1 in Neurotoxic Conditions Is Dependent on Serine Phosphorylation

Abstract

Calcium-dependent nuclear export of histone deacetylase 1 (HDAC1) was shown previously to precede axonal damage in culture, but the in vivo relevance of these findings and the potential posttranslational modifications of HDAC1 remained elusive. Using acute hippocampal slices from mice of either sex with genetic conditional ablation of Hdac1 in CA1 hippocampal neurons (i.e., Camk2a-cre;Hdac1 fl/fl ), we show significantly diminished axonal damage in response to neurotoxic stimuli. The protective effect of Hdac1 ablation was detected also in CA3 neurons in Grik4-cre;Hdac1 fl/f mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid. The amino acid residues modulating HDAC1 subcellular localization were identified by site-directed mutagenesis, which identified serine residues 421 and 423 as critical for its nuclear localization. The physiological phosphorylation of HDAC1 was decreased by neurotoxic stimuli, which stimulated the phosphatase enzymatic activity of calcineurin. Treatment of neurons with the calcineurin inhibitors FK506 or cyclosporin A resulted in nuclear accumulation of phospho-HDAC1 and was neuroprotective. Together, our data identify HDAC1 and the phosphorylation of specific serine residues in the molecule as potential targets for neuroprotection.

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…In that same study, the authors show that decreasing HDAC1 levels by genetic ablation was neuroprotective against acute neurotoxicity in hippocampal slices. The protective effect of Hdac1 ablation was also detected in CA3 neurons in mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid (Zhu et al 2017).…”

“…The protective effect of Hdac1 ablation was also detected in CA3 neurons in mice, which were more resistant to the excitotoxic damage induced by intraventricular injection of kainic acid (Zhu et al . ).…”

“…Other studies demonstrated that nuclear export of HDAC1 was dependent on post-translational modifications of HDAC1, whereby phosphorylation at Ser421 and Ser423 residues promoted nuclear export (Zhu et al 2017). In that same study, the authors show that decreasing HDAC1 levels by genetic ablation was neuroprotective against acute neurotoxicity in hippocampal slices.…”

Up‐regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide

“…So far, the endothelial phenotype in CKD has been extensively characterized, but there is a lack of information regarding the mechanisms through which the uraemic milieu exerts an impact on the endothelial cell and its epigenome. In this sense, several studies have shown that HDAC1 can also be expressed in the cytosol in different cell lines, [38][39][40] and although its expression is mainly located in the nucleus, its expression is enhanced in the cytosol in pathological conditions. We were able to identify two proteins, HDAC1 and HDAC2, involved in epigenetic regulation, among other up-regulated proteins.…”

Polymeric sheet actuators with programmable bioinstructivity

“…Mechanical stimuli of interstitial flow stimulated HDAC1 phosphorylation and increased the localization of phosphorylated HDAC1 (p-HDAC1) to the cytoplasm (38). Intracellular Ca 2+ inhibited nuclear localization and phosphorylation of HDAC1 (39,40). Here, the subcellular localization of p-HDAC1 was investigated by analyzing the fluorescence intensity of immunostained p-HDAC1 in cytosol and nuclei ( Fig.…”