Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated

Abstract Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not full...

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Autores principales:	Tanisha Singh, Yuanyuan Jiao, Lisa M. Ferrando, Svitlana Yablonska, Fang Li, Emily C. Horoszko, David Lacomis, Robert M. Friedlander, Diane L. Carlisle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/efa6a5cddeaf4ebbbd10ba1ac152d691
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spelling	oai:doaj.org-article:efa6a5cddeaf4ebbbd10ba1ac152d6912021-12-02T18:48:02ZNeuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated10.1038/s41598-021-97928-72045-2322https://doaj.org/article/efa6a5cddeaf4ebbbd10ba1ac152d6912021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97928-7https://doaj.org/toc/2045-2322Abstract Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not fully understood. We used human induced pluripotent stem cells and generated a developmental timeline by differentiating sALS iPSCs to neural progenitors and to motor neurons and comparing mitochondrial parameters with familial ALS (fALS) and control cells at each developmental stage. We report that sALS and fALS motor neurons have elevated reactive oxygen species levels, depolarized mitochondria, impaired oxidative phosphorylation, ATP loss and defective mitochondrial protein import compared with control motor neurons. This phenotype develops with differentiation into motor neurons, the affected cell type in ALS, and does not occur in the parental undifferentiated sALS cells or sALS neural progenitors. Our work demonstrates a developmentally regulated unifying mitochondrial phenotype between patient derived sALS and fALS motor neurons. The occurrence of a unifying mitochondrial phenotype suggests that mitochondrial etiology known to SOD1-fALS may applicable to sALS. Furthermore, our findings suggest that disease-modifying treatments focused on rescue of mitochondrial function may benefit both sALS and fALS patients.Tanisha SinghYuanyuan JiaoLisa M. FerrandoSvitlana YablonskaFang LiEmily C. HoroszkoDavid LacomisRobert M. FriedlanderDiane L. CarlisleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tanisha Singh Yuanyuan Jiao Lisa M. Ferrando Svitlana Yablonska Fang Li Emily C. Horoszko David Lacomis Robert M. Friedlander Diane L. Carlisle Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
description	Abstract Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not fully understood. We used human induced pluripotent stem cells and generated a developmental timeline by differentiating sALS iPSCs to neural progenitors and to motor neurons and comparing mitochondrial parameters with familial ALS (fALS) and control cells at each developmental stage. We report that sALS and fALS motor neurons have elevated reactive oxygen species levels, depolarized mitochondria, impaired oxidative phosphorylation, ATP loss and defective mitochondrial protein import compared with control motor neurons. This phenotype develops with differentiation into motor neurons, the affected cell type in ALS, and does not occur in the parental undifferentiated sALS cells or sALS neural progenitors. Our work demonstrates a developmentally regulated unifying mitochondrial phenotype between patient derived sALS and fALS motor neurons. The occurrence of a unifying mitochondrial phenotype suggests that mitochondrial etiology known to SOD1-fALS may applicable to sALS. Furthermore, our findings suggest that disease-modifying treatments focused on rescue of mitochondrial function may benefit both sALS and fALS patients.
format	article
author	Tanisha Singh Yuanyuan Jiao Lisa M. Ferrando Svitlana Yablonska Fang Li Emily C. Horoszko David Lacomis Robert M. Friedlander Diane L. Carlisle
author_facet	Tanisha Singh Yuanyuan Jiao Lisa M. Ferrando Svitlana Yablonska Fang Li Emily C. Horoszko David Lacomis Robert M. Friedlander Diane L. Carlisle
author_sort	Tanisha Singh
title	Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
title_short	Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
title_full	Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
title_fullStr	Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
title_full_unstemmed	Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
title_sort	neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/efa6a5cddeaf4ebbbd10ba1ac152d691
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Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated

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