Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons
dc.contributor.author | López de Maturana, Rakel | |
dc.contributor.author | Lang, Valérie | |
dc.contributor.author | Zubiarrain, Amaia | |
dc.contributor.author | Sousa, Amaya | |
dc.contributor.author | Vázquez, Nerea | |
dc.contributor.author | Gorostidi, Ana | |
dc.contributor.author | Águila, Julio | |
dc.contributor.author | López de Munain Arregui, Adolfo José | |
dc.contributor.author | Rodríguez, Manuel | |
dc.contributor.author | Sánchez-Pernaute, Rosario | |
dc.date.accessioned | 2019-04-09T12:42:48Z | |
dc.date.available | 2019-04-09T12:42:48Z | |
dc.date.issued | 2016-11-18 | |
dc.identifier.citation | Journal of Neuroimflammation 13 : (2016) // Article ID 295 | es_ES |
dc.identifier.issn | 1742-2094 | |
dc.identifier.uri | http://hdl.handle.net/10810/32385 | |
dc.description.abstract | Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. Methods: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2G2019S and LRRK2R1441G mutations. We used gene silencing and functional reporter assays to characterize the effect of the mutations. We examined the temporal profile of TNF alpha-induced changes in proteins of the NF-kappa B pathway and optimized western blot analysis to capture alpha-synuclein dynamics. The effects of the mutations and interventions were analyzed by two-way ANOVA tests with respect to corresponding controls. Results: LRRK2 silencing decreased alpha-synuclein protein levels in mutated neurons and modified NF-kappa B transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-kappa B and alpha-synuclein pathways converged and found that TNF alpha modulated alpha-synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-kappa B dysregulation in mutated neurons, as shown by a protracted recovery of I kappa B alpha and a clear impairment in p65 nuclear translocation in the LRRK2 mutants. Conclusions: Altogether, our results show that LRRK2 mutations affect alpha-synuclein regulation and impair NF-kappa B canonical signaling in iPSC-derived neurons. TNFa modulated alpha-synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PD | es_ES |
dc.description.sponsorship | This study is funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO), Fondo de Investigaciones Sanitarias PI15/00486, the European Commission FP7 Health -278871, and the Joint Program in Neurodegenerative Diseases AC 14/0041 (DAMNDPATHS) to RSP. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Biomed Central | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/ PI15/00486 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/FP7/278871 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | Parkinson's disease | es_ES |
dc.subject | LRRK2 | es_ES |
dc.subject | inflammation | es_ES |
dc.subject | iPSCs | es_ES |
dc.subject | NF-kappa B | es_ES |
dc.subject | alpha-Synuclein | es_ES |
dc.subject | dopamine neurons | es_ES |
dc.subject | inhibition | es_ES |
dc.subject | phosphorylation | es_ES |
dc.subject | inclusions | es_ES |
dc.subject | expression | es_ES |
dc.subject | interplay | es_ES |
dc.subject | autophagy | es_ES |
dc.subject | dementia | es_ES |
dc.title | Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0761-x | es_ES |
dc.identifier.doi | 10.1186/s12974-016-0761-x | |
dc.departamentoes | Neurociencias | es_ES |
dc.departamentoeu | Neurozientziak | es_ES |
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