miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/49651 |
Resumo: | Copyright © 2021 Oliveira, Dionísio, Gaspar, Correia Guedes, Coelho, Rosa, Ferreira, Amaral and Rodrigues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s diseaseLRRK2Parkinson’s diseaseInflammationmiR-335NecroptosisCopyright © 2021 Oliveira, Dionísio, Gaspar, Correia Guedes, Coelho, Rosa, Ferreira, Amaral and Rodrigues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the substantia nigra pars compacta accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase (LRRK2) gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD. Our results showed that miR-335 is significantly downregulated in different PD-mimicking conditions, including BV2 microglia cells stimulated with lipopolysaccharide (LPS) and/or overexpressing wild-type LRRK2. Importantly, these results were confirmed in serum of mice injected with 1-methyl-1-4-phenyl-1,2,3,6-tetrahydripyridine hydrochloride (MPTP), and further validated in patients with idiopathic PD (iPD) and those harboring mutations in LRRK2 (LRRK2-PD), thus corroborating potential clinical relevance. Mechanistically, miR-335 directly targeted LRRK2 mRNA. In the BV2 and N9 microglia cell lines, miR-335 strongly counteracted LPS-induced proinflammatory gene expression, and downregulated receptor interacting protein 1 (RIP1) and RIP3, two important players of necroptotic and inflammatory signaling pathways. Further, miR-335 inhibited LPS-mediated ERK1/2 activation. LRRK2-Wt-induced proinflammatory gene expression was also significantly reduced by miR-335 overexpression. Finally, in SH-SY5Y neuroblastoma cells, miR-335 decreased the expression of pro-inflammatory genes triggered by α-synuclein. In conclusion, we revealed novel roles for miR-335 in both microglia and neuronal cells that strongly halt the effects of classical inflammatory stimuli or LRRK2-Wt overexpression, thus attenuating chronic neuroinflammation.This research was funded in part by UIDB/04138/2020 from Fundação para a Ciência e Tecnologia (FCT), Portugal. SO received a Ph.D. fellowship (PD/BD/128332/2017) from FCT.FrontiersRepositório da Universidade de LisboaOliveira, SaraDionísio, Pedro A.Gaspar, Maria ManuelaCorreia Guedes, LeonorCoelho, MiguelRosa, Mário MiguelFerreira, Joaquim JAmaral, Joana D.Rodrigues, Cecília M. P.2021-09-27T15:43:53Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/49651engFront. Cell Dev. Biol. 9:661461.10.3389/fcell.2021.6614612296-634Xinfo: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:RCAAP2024-11-20T18:09:18Zoai:repositorio.ul.pt:10451/49651Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-20T18:09:18Repositório 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 |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
title |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
spellingShingle |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease Oliveira, Sara LRRK2 Parkinson’s disease Inflammation miR-335 Necroptosis |
title_short |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
title_full |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
title_fullStr |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
title_full_unstemmed |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
title_sort |
miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease |
author |
Oliveira, Sara |
author_facet |
Oliveira, Sara Dionísio, Pedro A. Gaspar, Maria Manuela Correia Guedes, Leonor Coelho, Miguel Rosa, Mário Miguel Ferreira, Joaquim J Amaral, Joana D. Rodrigues, Cecília M. P. |
author_role |
author |
author2 |
Dionísio, Pedro A. Gaspar, Maria Manuela Correia Guedes, Leonor Coelho, Miguel Rosa, Mário Miguel Ferreira, Joaquim J Amaral, Joana D. Rodrigues, Cecília M. P. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Oliveira, Sara Dionísio, Pedro A. Gaspar, Maria Manuela Correia Guedes, Leonor Coelho, Miguel Rosa, Mário Miguel Ferreira, Joaquim J Amaral, Joana D. Rodrigues, Cecília M. P. |
dc.subject.por.fl_str_mv |
LRRK2 Parkinson’s disease Inflammation miR-335 Necroptosis |
topic |
LRRK2 Parkinson’s disease Inflammation miR-335 Necroptosis |
description |
Copyright © 2021 Oliveira, Dionísio, Gaspar, Correia Guedes, Coelho, Rosa, Ferreira, Amaral and Rodrigues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-09-27T15:43:53Z 2021 2021-01-01T00:00:00Z |
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 |
http://hdl.handle.net/10451/49651 |
url |
http://hdl.handle.net/10451/49651 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Front. Cell Dev. Biol. 9:661461. 10.3389/fcell.2021.661461 2296-634X |
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 |
Frontiers |
publisher.none.fl_str_mv |
Frontiers |
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 |
repository.mail.fl_str_mv |
mluisa.alvim@gmail.com |
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1817549155145351168 |