Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Abstract Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acid...

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Autores principales:	James C. Dodge, Jinlong Yu, S. Pablo Sardi, Lamya S. Shihabuddin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0dc1212040940e185686c83d7cb49b3
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spelling	oai:doaj.org-article:a0dc1212040940e185686c83d7cb49b32021-12-02T14:01:24ZSterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis10.1038/s41598-020-80378-y2045-2322https://doaj.org/article/a0dc1212040940e185686c83d7cb49b32021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80378-yhttps://doaj.org/toc/2045-2322Abstract Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.James C. DodgeJinlong YuS. Pablo SardiLamya S. ShihabuddinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James C. Dodge Jinlong Yu S. Pablo Sardi Lamya S. Shihabuddin Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
description	Abstract Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.
format	article
author	James C. Dodge Jinlong Yu S. Pablo Sardi Lamya S. Shihabuddin
author_facet	James C. Dodge Jinlong Yu S. Pablo Sardi Lamya S. Shihabuddin
author_sort	James C. Dodge
title	Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
title_short	Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
title_full	Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
title_fullStr	Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
title_full_unstemmed	Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
title_sort	sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a0dc1212040940e185686c83d7cb49b3
work_keys_str_mv	AT jamescdodge sterolautooxidationadverselyaffectshumanmotorneuronviabilityandisaneuropathologicalfeatureofamyotrophiclateralsclerosis AT jinlongyu sterolautooxidationadverselyaffectshumanmotorneuronviabilityandisaneuropathologicalfeatureofamyotrophiclateralsclerosis AT spablosardi sterolautooxidationadverselyaffectshumanmotorneuronviabilityandisaneuropathologicalfeatureofamyotrophiclateralsclerosis AT lamyasshihabuddin sterolautooxidationadverselyaffectshumanmotorneuronviabilityandisaneuropathologicalfeatureofamyotrophiclateralsclerosis
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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

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