BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we us...

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Autores principales:	Marta Gómez-Almería, Sonia Burgaz, Carlos Costas-Insua, Carmen Rodríguez-Cueto, Irene Santos-García, Ignacio Rodríguez-Crespo, Concepción García, Manuel Guzmán, Eva de Lago, Javier Fernández-Ruiz
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cannabinoids CB<sub>1</sub> receptors BiP interactor protein BiP<sup>+/−</sup> mice mSOD1 mice amyotrophic lateral sclerosis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0596c9acd46f48c0a93625dc3145c5b7
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spelling	oai:doaj.org-article:0596c9acd46f48c0a93625dc3145c5b72021-11-25T17:57:34ZBiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis10.3390/ijms2222125331422-00671661-6596https://doaj.org/article/0596c9acd46f48c0a93625dc3145c5b72021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12533https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP<sup>+/−</sup> mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP<sup>+/−</sup> double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP<sup>+/−</sup> mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP<sup>+/−</sup> mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB<sub>1</sub>) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB<sub>1</sub> receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.Marta Gómez-AlmeríaSonia BurgazCarlos Costas-InsuaCarmen Rodríguez-CuetoIrene Santos-GarcíaIgnacio Rodríguez-CrespoConcepción GarcíaManuel GuzmánEva de LagoJavier Fernández-RuizMDPI AGarticlecannabinoidsCB<sub>1</sub> receptorsBiP interactor proteinBiP<sup>+/−</sup> micemSOD1 miceamyotrophic lateral sclerosisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12533, p 12533 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cannabinoids CB<sub>1</sub> receptors BiP interactor protein BiP<sup>+/−</sup> mice mSOD1 mice amyotrophic lateral sclerosis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	cannabinoids CB<sub>1</sub> receptors BiP interactor protein BiP<sup>+/−</sup> mice mSOD1 mice amyotrophic lateral sclerosis Biology (General) QH301-705.5 Chemistry QD1-999 Marta Gómez-Almería Sonia Burgaz Carlos Costas-Insua Carmen Rodríguez-Cueto Irene Santos-García Ignacio Rodríguez-Crespo Concepción García Manuel Guzmán Eva de Lago Javier Fernández-Ruiz BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
description	In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP<sup>+/−</sup> mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP<sup>+/−</sup> double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP<sup>+/−</sup> mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP<sup>+/−</sup> mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB<sub>1</sub>) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB<sub>1</sub> receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.
format	article
author	Marta Gómez-Almería Sonia Burgaz Carlos Costas-Insua Carmen Rodríguez-Cueto Irene Santos-García Ignacio Rodríguez-Crespo Concepción García Manuel Guzmán Eva de Lago Javier Fernández-Ruiz
author_facet	Marta Gómez-Almería Sonia Burgaz Carlos Costas-Insua Carmen Rodríguez-Cueto Irene Santos-García Ignacio Rodríguez-Crespo Concepción García Manuel Guzmán Eva de Lago Javier Fernández-Ruiz
author_sort	Marta Gómez-Almería
title	BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
title_short	BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
title_full	BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
title_fullStr	BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
title_full_unstemmed	BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
title_sort	bip heterozigosity aggravates pathological deterioration in experimental amyotrophic lateral sclerosis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0596c9acd46f48c0a93625dc3145c5b7
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BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis

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