Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/111128 |
Resumo: | Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper (cortical) and lower (spinal cord, SC) motor neurons (MNs) and aberrancy of glial cells. Results from our group point to a close connection between increased levels of miRNA-124 and the acquisition of pathological characteristics in MNs, astrocytes and microglia in ALS. Our main aim was to validate if the downregulation of the elevated levels of miR-124 in hSOD1G93A (mSOD1) MNs toward normal levels was preventive over neurodegeneration, astrocyte aberrancies and microglia activation in the mSOD1 mice at the early onset of the disease (10-12 weeks). Two ALS models were used: the NSC-34 MN-like cell line expressing mSOD1 (transgenic, TG) or not (wild-type, WT); and the SC organotypic cultures (OCs) from WT and TG mice. Pathological differences between TG and WT SCOCs were investigated. Relatively to the MN models, we used the modulation with pre-miR-124 (only in WT) and that of anti-miR-124 (only in the TG). The isolated secretomes were incubated in WT and TG SCOCs to assess harmful and/or neuroprotective properties. In TG SCOCs we observed: (i) increased necrotic cell death; (ii) disturbed inflammatory-associated miRNAs (increase in miR-21/miR-146a); (iii) and dysregulated neuronal and glial genes (increased CX3CR1, IL-1β, IL-10, SYP, DRP1, GLT-1 and downregulation of iNOS, HMGB1, Dlg4, CX3CL1 and GFAP). WT-MN secretome counteracted pathological markers in TG SCOCs. In contrast, TG MN secretome induced deleterious effects in WT SCOCs. Secretome from miR-124-enriched WT MNs incubated in WT SCOCs led to a profile of miRNAs and protein-coding genes similar to that caused by the TG MN secretome. On the contrary, the secretome from TG MNs depleted in miR-124 restored a deactivated profile in TG SCOCs. Our data reveals MN upregulation of miR-124 as a key player in ALS pathological processes. |
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Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse modelsAmyotrophic lateral sclerosisMotor neuronGlial cellsmiR-124 modulationSecretomeSpinal cord organotypic culturesDomínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e TecnologiasAmyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper (cortical) and lower (spinal cord, SC) motor neurons (MNs) and aberrancy of glial cells. Results from our group point to a close connection between increased levels of miRNA-124 and the acquisition of pathological characteristics in MNs, astrocytes and microglia in ALS. Our main aim was to validate if the downregulation of the elevated levels of miR-124 in hSOD1G93A (mSOD1) MNs toward normal levels was preventive over neurodegeneration, astrocyte aberrancies and microglia activation in the mSOD1 mice at the early onset of the disease (10-12 weeks). Two ALS models were used: the NSC-34 MN-like cell line expressing mSOD1 (transgenic, TG) or not (wild-type, WT); and the SC organotypic cultures (OCs) from WT and TG mice. Pathological differences between TG and WT SCOCs were investigated. Relatively to the MN models, we used the modulation with pre-miR-124 (only in WT) and that of anti-miR-124 (only in the TG). The isolated secretomes were incubated in WT and TG SCOCs to assess harmful and/or neuroprotective properties. In TG SCOCs we observed: (i) increased necrotic cell death; (ii) disturbed inflammatory-associated miRNAs (increase in miR-21/miR-146a); (iii) and dysregulated neuronal and glial genes (increased CX3CR1, IL-1β, IL-10, SYP, DRP1, GLT-1 and downregulation of iNOS, HMGB1, Dlg4, CX3CL1 and GFAP). WT-MN secretome counteracted pathological markers in TG SCOCs. In contrast, TG MN secretome induced deleterious effects in WT SCOCs. Secretome from miR-124-enriched WT MNs incubated in WT SCOCs led to a profile of miRNAs and protein-coding genes similar to that caused by the TG MN secretome. On the contrary, the secretome from TG MNs depleted in miR-124 restored a deactivated profile in TG SCOCs. Our data reveals MN upregulation of miR-124 as a key player in ALS pathological processes.Casa da Misericórdia de Lisboa (SCML), project ref. ALSResearch Grant ELA-2015-002Brites, DoraBotelho, Ana RitaBraga, MargaridaRUNMorais, Hermes Manuel Medina2023-12-02T01:30:47Z2021-01-1120202021-01-11T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/111128enginfo: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:RCAAP2024-03-11T04:54:56Zoai:run.unl.pt:10362/111128Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:41:48.518563Repositório 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 |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
title |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
spellingShingle |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models Morais, Hermes Manuel Medina Amyotrophic lateral sclerosis Motor neuron Glial cells miR-124 modulation Secretome Spinal cord organotypic cultures Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
title_short |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
title_full |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
title_fullStr |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
title_full_unstemmed |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
title_sort |
Development of secretome-based therapy by motor neuron modulation of miRNA-124 in ALS mouse models |
author |
Morais, Hermes Manuel Medina |
author_facet |
Morais, Hermes Manuel Medina |
author_role |
author |
dc.contributor.none.fl_str_mv |
Brites, Dora Botelho, Ana Rita Braga, Margarida RUN |
dc.contributor.author.fl_str_mv |
Morais, Hermes Manuel Medina |
dc.subject.por.fl_str_mv |
Amyotrophic lateral sclerosis Motor neuron Glial cells miR-124 modulation Secretome Spinal cord organotypic cultures Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
topic |
Amyotrophic lateral sclerosis Motor neuron Glial cells miR-124 modulation Secretome Spinal cord organotypic cultures Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias |
description |
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper (cortical) and lower (spinal cord, SC) motor neurons (MNs) and aberrancy of glial cells. Results from our group point to a close connection between increased levels of miRNA-124 and the acquisition of pathological characteristics in MNs, astrocytes and microglia in ALS. Our main aim was to validate if the downregulation of the elevated levels of miR-124 in hSOD1G93A (mSOD1) MNs toward normal levels was preventive over neurodegeneration, astrocyte aberrancies and microglia activation in the mSOD1 mice at the early onset of the disease (10-12 weeks). Two ALS models were used: the NSC-34 MN-like cell line expressing mSOD1 (transgenic, TG) or not (wild-type, WT); and the SC organotypic cultures (OCs) from WT and TG mice. Pathological differences between TG and WT SCOCs were investigated. Relatively to the MN models, we used the modulation with pre-miR-124 (only in WT) and that of anti-miR-124 (only in the TG). The isolated secretomes were incubated in WT and TG SCOCs to assess harmful and/or neuroprotective properties. In TG SCOCs we observed: (i) increased necrotic cell death; (ii) disturbed inflammatory-associated miRNAs (increase in miR-21/miR-146a); (iii) and dysregulated neuronal and glial genes (increased CX3CR1, IL-1β, IL-10, SYP, DRP1, GLT-1 and downregulation of iNOS, HMGB1, Dlg4, CX3CL1 and GFAP). WT-MN secretome counteracted pathological markers in TG SCOCs. In contrast, TG MN secretome induced deleterious effects in WT SCOCs. Secretome from miR-124-enriched WT MNs incubated in WT SCOCs led to a profile of miRNAs and protein-coding genes similar to that caused by the TG MN secretome. On the contrary, the secretome from TG MNs depleted in miR-124 restored a deactivated profile in TG SCOCs. Our data reveals MN upregulation of miR-124 as a key player in ALS pathological processes. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020 2021-01-11 2021-01-11T00:00:00Z 2023-12-02T01:30:47Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/111128 |
url |
http://hdl.handle.net/10362/111128 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
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.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 |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799138030946091008 |