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miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson’s Disease
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 repea...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239393/ https://www.ncbi.nlm.nih.gov/pubmed/34211970 http://dx.doi.org/10.3389/fcell.2021.661461 |
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author | Oliveira, Sara R. Dionísio, Pedro A. Gaspar, Maria M. Correia Guedes, Leonor Coelho, Miguel Rosa, Mário M. Ferreira, Joaquim J. Amaral, Joana D. Rodrigues, Cecília M. P. |
author_facet | Oliveira, Sara R. Dionísio, Pedro A. Gaspar, Maria M. Correia Guedes, Leonor Coelho, Miguel Rosa, Mário M. Ferreira, Joaquim J. Amaral, Joana D. Rodrigues, Cecília M. P. |
author_sort | Oliveira, Sara R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8239393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82393932021-06-30 miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson’s Disease Oliveira, Sara R. Dionísio, Pedro A. Gaspar, Maria M. Correia Guedes, Leonor Coelho, Miguel Rosa, Mário M. Ferreira, Joaquim J. Amaral, Joana D. Rodrigues, Cecília M. P. Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-06-15 /pmc/articles/PMC8239393/ /pubmed/34211970 http://dx.doi.org/10.3389/fcell.2021.661461 Text en Copyright © 2021 Oliveira, Dionísio, Gaspar, Correia Guedes, Coelho, Rosa, Ferreira, Amaral and Rodrigues. https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Cell and Developmental Biology Oliveira, Sara R. Dionísio, Pedro A. Gaspar, Maria M. Correia Guedes, Leonor Coelho, Miguel Rosa, Mário M. Ferreira, Joaquim J. Amaral, Joana D. Rodrigues, Cecília M. P. miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson’s Disease |
title | 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_short | miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson’s Disease |
title_sort | mir-335 targets lrrk2 and mitigates inflammation in parkinson’s disease |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239393/ https://www.ncbi.nlm.nih.gov/pubmed/34211970 http://dx.doi.org/10.3389/fcell.2021.661461 |
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