Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis

Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compro...

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Autores: Casas Louzao, Caty|||0000-0002-2273-6321, Herrando-Grabulosa, Mireia|||0000-0002-6685-3220, Manzano Martínez, Raquel|||0000-0002-7477-8742, Mancuso, Renzo|||0000-0002-7046-3348, Osta, Rosario|||0000-0001-5687-6704, Navarro, X. (Xavier)|||0000-0001-9849-902X
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:184914
Acceso en línea:https://ddd.uab.cat/record/184914
https://dx.doi.org/urn:doi:10.1002/brb3.104
Access Level:acceso abierto
Palabra clave:Amyotrophic lateral sclerosis
ChAT
MHC-I
Motoneuron
Presynaptic boutons
Tdp-43
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spelling Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosisCasas Louzao, Caty|||0000-0002-2273-6321Herrando-Grabulosa, Mireia|||0000-0002-6685-3220Manzano Martínez, Raquel|||0000-0002-7477-8742Mancuso, Renzo|||0000-0002-7046-3348Osta, Rosario|||0000-0001-5687-6704Navarro, X. (Xavier)|||0000-0001-9849-902XAmyotrophic lateral sclerosisChATMHC-IMotoneuronPresynaptic boutonsTdp-43Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1 G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1 G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis. 22013-01-0120132013-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/184914https://dx.doi.org/urn:doi:10.1002/brb3.104reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2009-12495open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1849142026-06-06T12:50:31Z
dc.title.none.fl_str_mv Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
title Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
spellingShingle Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
Casas Louzao, Caty|||0000-0002-2273-6321
Amyotrophic lateral sclerosis
ChAT
MHC-I
Motoneuron
Presynaptic boutons
Tdp-43
title_short Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
title_full Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
title_fullStr Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
title_full_unstemmed Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
title_sort Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis
dc.creator.none.fl_str_mv Casas Louzao, Caty|||0000-0002-2273-6321
Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Manzano Martínez, Raquel|||0000-0002-7477-8742
Mancuso, Renzo|||0000-0002-7046-3348
Osta, Rosario|||0000-0001-5687-6704
Navarro, X. (Xavier)|||0000-0001-9849-902X
author Casas Louzao, Caty|||0000-0002-2273-6321
author_facet Casas Louzao, Caty|||0000-0002-2273-6321
Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Manzano Martínez, Raquel|||0000-0002-7477-8742
Mancuso, Renzo|||0000-0002-7046-3348
Osta, Rosario|||0000-0001-5687-6704
Navarro, X. (Xavier)|||0000-0001-9849-902X
author_role author
author2 Herrando-Grabulosa, Mireia|||0000-0002-6685-3220
Manzano Martínez, Raquel|||0000-0002-7477-8742
Mancuso, Renzo|||0000-0002-7046-3348
Osta, Rosario|||0000-0001-5687-6704
Navarro, X. (Xavier)|||0000-0001-9849-902X
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Amyotrophic lateral sclerosis
ChAT
MHC-I
Motoneuron
Presynaptic boutons
Tdp-43
topic Amyotrophic lateral sclerosis
ChAT
MHC-I
Motoneuron
Presynaptic boutons
Tdp-43
description Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1 G93A ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1 G93A mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis.
publishDate 2013
dc.date.none.fl_str_mv 2
2013-01-01
2013
2013-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/184914
https://dx.doi.org/urn:doi:10.1002/brb3.104
url https://ddd.uab.cat/record/184914
https://dx.doi.org/urn:doi:10.1002/brb3.104
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2009-12495
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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