Small chaperons and autophagy protected neurons from necrotic cell death

Abstract Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression o...

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Autores principales:	Ye Lei, Kai Liu, Lin Hou, Lianggong Ding, Yuhong Li, Lei Liu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/549da4f68923482d8e3fa100a2a1be22
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spelling	oai:doaj.org-article:549da4f68923482d8e3fa100a2a1be222021-12-02T15:05:14ZSmall chaperons and autophagy protected neurons from necrotic cell death10.1038/s41598-017-05995-62045-2322https://doaj.org/article/549da4f68923482d8e3fa100a2a1be222017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05995-6https://doaj.org/toc/2045-2322Abstract Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression of a constitutively opened cation channel mutant. Here, we performed further genetic screens and identified a suppressor of neuronal necrosis, CG17259, which encodes a seryl-tRNA synthetase. We found that loss-of-function (LOF) CG17259 activated eIF2α phosphorylation and subsequent up-regulation of chaperons (Hsp26 and Hsp27) and autophagy. Genetically, down-regulation of eIF2α phosphorylation, Hsp26/Hsp27 or autophagy reduced the protective effect of LOF CG17259, indicating they function downstream of CG17259. The protective effect of these protein degradation pathways indicated activation of a toxic protein during neuronal necrosis. Our data indicated that p53 was likely one such protein, because p53 was accumulated in the necrotic neurons and down-regulation of p53 rescued necrosis. In the SH-SY5Y human cells, tunicamycin (TM), a PERK activator, promoted transcription of hsp27; and necrosis induced by glutamate could be rescued by TM, associated with reduced p53 accumulation. In an ischemic stroke model in rats, p53 protein was also increased, and TM treatment could reduce the p53 accumulation and brain damage.Ye LeiKai LiuLin HouLianggong DingYuhong LiLei LiuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ye Lei Kai Liu Lin Hou Lianggong Ding Yuhong Li Lei Liu Small chaperons and autophagy protected neurons from necrotic cell death
description	Abstract Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression of a constitutively opened cation channel mutant. Here, we performed further genetic screens and identified a suppressor of neuronal necrosis, CG17259, which encodes a seryl-tRNA synthetase. We found that loss-of-function (LOF) CG17259 activated eIF2α phosphorylation and subsequent up-regulation of chaperons (Hsp26 and Hsp27) and autophagy. Genetically, down-regulation of eIF2α phosphorylation, Hsp26/Hsp27 or autophagy reduced the protective effect of LOF CG17259, indicating they function downstream of CG17259. The protective effect of these protein degradation pathways indicated activation of a toxic protein during neuronal necrosis. Our data indicated that p53 was likely one such protein, because p53 was accumulated in the necrotic neurons and down-regulation of p53 rescued necrosis. In the SH-SY5Y human cells, tunicamycin (TM), a PERK activator, promoted transcription of hsp27; and necrosis induced by glutamate could be rescued by TM, associated with reduced p53 accumulation. In an ischemic stroke model in rats, p53 protein was also increased, and TM treatment could reduce the p53 accumulation and brain damage.
format	article
author	Ye Lei Kai Liu Lin Hou Lianggong Ding Yuhong Li Lei Liu
author_facet	Ye Lei Kai Liu Lin Hou Lianggong Ding Yuhong Li Lei Liu
author_sort	Ye Lei
title	Small chaperons and autophagy protected neurons from necrotic cell death
title_short	Small chaperons and autophagy protected neurons from necrotic cell death
title_full	Small chaperons and autophagy protected neurons from necrotic cell death
title_fullStr	Small chaperons and autophagy protected neurons from necrotic cell death
title_full_unstemmed	Small chaperons and autophagy protected neurons from necrotic cell death
title_sort	small chaperons and autophagy protected neurons from necrotic cell death
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/549da4f68923482d8e3fa100a2a1be22
work_keys_str_mv	AT yelei smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath AT kailiu smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath AT linhou smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath AT lianggongding smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath AT yuhongli smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath AT leiliu smallchaperonsandautophagyprotectedneuronsfromnecroticcelldeath
_version_	1718388890354581504

Small chaperons and autophagy protected neurons from necrotic cell death

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