Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice

Abstract Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degenerati...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Liuji Chen, Ren Na, Kirsten Danae McLane, Cody Sylvester Thompson, Ju Gao, Xinglong Wang, Qitao Ran
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fe6808cd5a064594a9ab55d65bc77191
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:fe6808cd5a064594a9ab55d65bc77191
record_format	dspace
spelling	oai:doaj.org-article:fe6808cd5a064594a9ab55d65bc771912021-12-02T16:04:35ZOverexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice10.1038/s41598-021-92369-82045-2322https://doaj.org/article/fe6808cd5a064594a9ab55d65bc771912021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92369-8https://doaj.org/toc/2045-2322Abstract Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1G93A mice, a widely used ALS mouse model. Compared with control SOD1G93A mice, both male and female SOD1G93AGPX4 mice had extended lifespans. SOD1G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.Liuji ChenRen NaKirsten Danae McLaneCody Sylvester ThompsonJu GaoXinglong WangQitao RanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Liuji Chen Ren Na Kirsten Danae McLane Cody Sylvester Thompson Ju Gao Xinglong Wang Qitao Ran Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
description	Abstract Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1G93A mice, a widely used ALS mouse model. Compared with control SOD1G93A mice, both male and female SOD1G93AGPX4 mice had extended lifespans. SOD1G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.
format	article
author	Liuji Chen Ren Na Kirsten Danae McLane Cody Sylvester Thompson Ju Gao Xinglong Wang Qitao Ran
author_facet	Liuji Chen Ren Na Kirsten Danae McLane Cody Sylvester Thompson Ju Gao Xinglong Wang Qitao Ran
author_sort	Liuji Chen
title	Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
title_short	Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
title_full	Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
title_fullStr	Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
title_full_unstemmed	Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice
title_sort	overexpression of ferroptosis defense enzyme gpx4 retards motor neuron disease of sod1g93a mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fe6808cd5a064594a9ab55d65bc77191
work_keys_str_mv	AT liujichen overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT renna overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT kirstendanaemclane overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT codysylvesterthompson overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT jugao overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT xinglongwang overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice AT qitaoran overexpressionofferroptosisdefenseenzymegpx4retardsmotorneurondiseaseofsod1g93amice
_version_	1718385247566954496

Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice

Ejemplares similares