Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/80728 |
Resumo: | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model. |
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Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A miceALS mouse modelAnti-microRNA-124Intraspinal delivery routeNeuroprotectionPrevention of glial dysfunctionPreservation of motor performanceSecretome-based therapySOD1-G93A mutationScience & TechnologyAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.This research was funded by Santa Casa da Misericórdia de Lisboa: ELA-2015-002 (to DB); Fundação para a Ciência e a Tecnologia (FCT): PTDC/MED-NEU/31395/2017 (to D.B.), UIDB/UIDP/04138/2020, and UID/DTP/04138/2019-2020 (to iMed.ULisboa); Programa Operacional Regional de Lisboa and the Programa Operacional Competitividade e Internacionalização LISBOA-01-0145-FEDER-031395 (to D.B.); La Caixa Foundation and Francisco Luzón Foundation through project HR21-00931 (to D.B.); and an individual fellowship from FCT: SFRH/BD/129586/2017 (to M.B.). This work was also funded by the ICVS Scientific Microscopy Platform, a member of the national infrastructure of PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122).Multidisciplinary Digital Publishing Institute (MDPI)Universidade do MinhoBarbosa, MartaSantos, Martade Sousa, NídiaSilva, Sara Carina DuarteVaz, Ana RitaSalgado, A. J.Brites, Dora2022-08-292022-08-29T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/80728engBarbosa, M.; Santos, M.; de Sousa, N.; Duarte-Silva, S.; Vaz, A.R.; Salgado, A.J.; Brites, D. Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice. Biomedicines 2022, 10, 2120. https://doi.org/10.3390/biomedicines100921202227-905910.3390/biomedicines100921202120https://www.mdpi.com/2227-9059/10/9/2120info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:06:59Zoai:repositorium.sdum.uminho.pt:1822/80728Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:57:48.911591Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
title |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
spellingShingle |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice Barbosa, Marta ALS mouse model Anti-microRNA-124 Intraspinal delivery route Neuroprotection Prevention of glial dysfunction Preservation of motor performance Secretome-based therapy SOD1-G93A mutation Science & Technology |
title_short |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
title_full |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
title_fullStr |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
title_full_unstemmed |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
title_sort |
Intrathecal injection of the secretome from ALS motor neurons regulated for miR-124 expression prevents disease outcomes in SOD1-G93A mice |
author |
Barbosa, Marta |
author_facet |
Barbosa, Marta Santos, Marta de Sousa, Nídia Silva, Sara Carina Duarte Vaz, Ana Rita Salgado, A. J. Brites, Dora |
author_role |
author |
author2 |
Santos, Marta de Sousa, Nídia Silva, Sara Carina Duarte Vaz, Ana Rita Salgado, A. J. Brites, Dora |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Barbosa, Marta Santos, Marta de Sousa, Nídia Silva, Sara Carina Duarte Vaz, Ana Rita Salgado, A. J. Brites, Dora |
dc.subject.por.fl_str_mv |
ALS mouse model Anti-microRNA-124 Intraspinal delivery route Neuroprotection Prevention of glial dysfunction Preservation of motor performance Secretome-based therapy SOD1-G93A mutation Science & Technology |
topic |
ALS mouse model Anti-microRNA-124 Intraspinal delivery route Neuroprotection Prevention of glial dysfunction Preservation of motor performance Secretome-based therapy SOD1-G93A mutation Science & Technology |
description |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-08-29 2022-08-29T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/80728 |
url |
https://hdl.handle.net/1822/80728 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Barbosa, M.; Santos, M.; de Sousa, N.; Duarte-Silva, S.; Vaz, A.R.; Salgado, A.J.; Brites, D. Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice. Biomedicines 2022, 10, 2120. https://doi.org/10.3390/biomedicines10092120 2227-9059 10.3390/biomedicines10092120 2120 https://www.mdpi.com/2227-9059/10/9/2120 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute (MDPI) |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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