Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previ...

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Autores principales:	Yafa Fetfet Malada Edelstein, Yulia Solomonov, Nurit Hadad, Leenor Alfahel, Adrian Israelson, Rachel Levy
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Cytosolic phospholipase A2α ALS Mutant SOD1G93A Motor neurons TNFα Misfolded SOD1 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/a92dd4b6023c46f99cde3f6de6d2c91d
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spelling	oai:doaj.org-article:a92dd4b6023c46f99cde3f6de6d2c91d2021-11-28T12:37:41ZEarly upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis10.1186/s12974-021-02326-51742-2094https://doaj.org/article/a92dd4b6023c46f99cde3f6de6d2c91d2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02326-5https://doaj.org/toc/1742-2094Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.Yafa Fetfet Malada EdelsteinYulia SolomonovNurit HadadLeenor AlfahelAdrian IsraelsonRachel LevyBMCarticleCytosolic phospholipase A2αALSMutant SOD1G93AMotor neuronsTNFαMisfolded SOD1Neurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytosolic phospholipase A2α ALS Mutant SOD1G93A Motor neurons TNFα Misfolded SOD1 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Cytosolic phospholipase A2α ALS Mutant SOD1G93A Motor neurons TNFα Misfolded SOD1 Neurology. Diseases of the nervous system RC346-429 Yafa Fetfet Malada Edelstein Yulia Solomonov Nurit Hadad Leenor Alfahel Adrian Israelson Rachel Levy Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
description	Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.
format	article
author	Yafa Fetfet Malada Edelstein Yulia Solomonov Nurit Hadad Leenor Alfahel Adrian Israelson Rachel Levy
author_facet	Yafa Fetfet Malada Edelstein Yulia Solomonov Nurit Hadad Leenor Alfahel Adrian Israelson Rachel Levy
author_sort	Yafa Fetfet Malada Edelstein
title	Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
title_short	Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
title_full	Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
title_fullStr	Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
title_full_unstemmed	Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis
title_sort	early upregulation of cytosolic phospholipase a2α in motor neurons is induced by misfolded sod1 in a mouse model of amyotrophic lateral sclerosis
publisher	BMC
publishDate	2021
url	https://doaj.org/article/a92dd4b6023c46f99cde3f6de6d2c91d
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Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

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