Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration

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• dc.contributor.author Carola, Giulia
• dc.contributor.author Malagarriga, Daniel
• dc.contributor.author Calatayud, Carles
• dc.contributor.author Pons Espinal, Meritxell, 1986-
• dc.contributor.author Blasco Agell, Lucas
• dc.contributor.author Richaud Patin, Yvonne
• dc.contributor.author Fernández Carasa, Irene
• dc.contributor.author Baruffi, Valentina
• dc.contributor.author Beltramone, Santiago
• dc.contributor.author Molina, Emilio
• dc.contributor.author Dell'Era, Patrizia
• dc.contributor.author Toledo Aral, Juan J.
• dc.contributor.author Tolosa, Eduard
• dc.contributor.author Muotri, Alysson R.
• dc.contributor.author García Ojalvo, Jordi
• dc.contributor.author Soriano Fradera, Jordi
• dc.contributor.author Raya Chamorro, Ángel
• dc.contributor.author Consiglio, Antonella
• dc.date.accessioned 2021-08-06T06:04:29Z
• dc.date.available 2021-08-06T06:04:29Z
• dc.date.issued 2021
• dc.description.abstract A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.
• dc.description.sponsorship Research from the authors’ laboratories is supported by the European Research Council-ERC (2012-StG-311736-PD-HUMMODEL), the MESOBRAIN project from the European Union’s Horizon 2020 research and innovation (grant agreement No. 713140), the Spanish Ministry of Economy and Competitiveness-MINECO (RTI2018-095377-B-100, FIS2016-78507-C2-2-P, PID2019-108842GB-C21) the Spanish Ministry of Economy and Competitiveness-MINECO/AEI/FEDER, UE (BFU2016-80870-P) and the Spanish Ministry of Economy and Competitiveness- AEI/10.13039/501100011033 (PID2019-108792GB-I00), Instituto de Salud Carlos III-ISCIII/FEDER (Red de Terapia Celular - TerCel RD16/0011/0024 and RD16/0011/0025), AGAUR (2017-SGR-899 and 2017-SGR-1061), and CERCA Program/Generalitat de Catalunya. M.P.E. was partially supported by a Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR) of the Government of Catalonia (2017 BP 00133). L.B. is the recipient of a pre-doctoral fellowship FPI (BES-2017-080579) from the Spanish Ministry of Economy and Competitiveness (MINECO). G.C. was partially supported by pre-doctoral fellowship from Spanish Economy and Competitiveness-MINECO (BES-2014-069603).
• dc.format.mimetype application/pdf
• dc.identifier.citation Carola G, Malagarriga D, Calatayud C, Pons-Espinal M, Blasco-Agell L, Richaud-Patin Y, Fernandez-Carasa I, Baruffi V, Beltramone S, Molina E, Dell'Era P, Toledo-Aral JJ, Tolosa E, Muotri AR, Garcia Ojalvo J, Soriano J, Raya A, Consiglio A. Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration. NPJ Parkinsons Dis. 2021;7(1):55. DOI: 10.1038/s41531-021-00198-3
• dc.identifier.doi http://dx.doi.org/10.1038/s41531-021-00198-3
• dc.identifier.issn 2373-8057
• dc.identifier.uri http://hdl.handle.net/10230/48322
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof NPJ Parkinsons Dis. 2021;7(1):55
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/713140
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-095377-B-100
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/FIS2016-78507-C2-2-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108842GB-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-80870-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108792GB-I00
• dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Diseases of the nervous system
• dc.subject.keyword Neuroscience
• dc.title Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion