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miR-335 targets LRRK2 and mitigates inflammation in Parkinson’s disease

2021Artigo científico Acesso aberto
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dc.contributor.authorOliveira, Sara
dc.contributor.authorDionísio, Pedro A.
dc.contributor.authorGaspar, Maria Manuela
dc.contributor.authorCorreia Guedes, Leonor
dc.contributor.authorCoelho, Miguel
dc.contributor.authorRosa, Mário Miguel
dc.contributor.authorFerreira, Joaquim J
dc.contributor.authorAmaral, Joana D.
dc.contributor.authorRodrigues, Cecília M. P.
dc.date.accessioned2021-09-27T15:43:53Z
dc.date.available2021-09-27T15:43:53Z
dc.date.issued2021
dc.descriptionCopyright © 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.pt_PT
dc.description.abstractParkinson'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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront. Cell Dev. Biol. 9:661461.pt_PT
dc.identifier.doi10.3389/fcell.2021.661461pt_PT
dc.identifier.eissn2296-634X
dc.identifier.urihttp://hdl.handle.net/10451/49651
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relation.publisherversionhttps://www.frontiersin.org/journals/cell-and-developmental-biologypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectLRRK2pt_PT
dc.subjectParkinson’s diseasept_PT
dc.subjectInflammationpt_PT
dc.subjectmiR-335pt_PT
dc.subjectNecroptosispt_PT
dc.titlemiR-335 targets LRRK2 and mitigates inflammation in Parkinson’s diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/157522/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/59869/PT
oaire.citation.titleFrontiers in Cell and Developmental Biologypt_PT
oaire.citation.volume9pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameRodrigues Oliveira
person.familyNameAntunes Dionísio
person.familyNamede Jesus Guilherme Gaspar
person.familyNameCorreia Guedes
person.familyNameCoelho
person.familyNameCOELHO DA SILVA ROSA
person.familyNameFerreira
person.familyNameSão José Dias Amaral
person.familyNameRodrigues
person.givenNameSara
person.givenNamePedro Elói
person.givenNameMaria Manuela
person.givenNameLeonor
person.givenNameMiguel
person.givenNameMÁRIO MIGUEL
person.givenNameJoaquim J
person.givenNameJoana
person.givenNameCecilia
person.identifierC-2024-2014
person.identifier1624753
person.identifierM-4660-2013
person.identifier30919
person.identifier.ciencia-idD615-388C-5C57
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person.identifier.ciencia-id3A10-0732-13F5
person.identifier.ciencia-id1518-348B-19BD
person.identifier.ciencia-id3312-A6EB-631D
person.identifier.ciencia-idAD12-9209-3302
person.identifier.ciencia-id7D15-5CD6-6159
person.identifier.ciencia-id641A-6130-88ED
person.identifier.ciencia-idDC18-39A7-F287
person.identifier.orcid0000-0002-3433-6712
person.identifier.orcid0000-0003-2756-1863
person.identifier.orcid0000-0001-6814-7226
person.identifier.orcid0000-0002-8422-0494
person.identifier.orcid0000-0002-4008-8110
person.identifier.orcid0000-0003-3158-2106
person.identifier.orcid0000-0003-3950-5113
person.identifier.orcid0000-0001-9504-5102
person.identifier.orcid0000-0002-4829-754X
person.identifier.ridM-3572-2013
person.identifier.scopus-author-id55549279900
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person.identifier.scopus-author-id7101666975
person.identifier.scopus-author-id7403252466
person.identifier.scopus-author-id8912000100
person.identifier.scopus-author-id7202508239
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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