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

Carola, GiuliaMalagarriga, DanielCalatayud, CarlesPons Espinal, Meritxell, 1986-Blasco Agell, LucasRichaud Patin, YvonneFernández Carasa, IreneBaruffi, ValentinaBeltramone, SantiagoMolina, EmilioDell'Era, PatriziaToledo Aral, Juan J.Tolosa, EduardMuotri, Alysson R.García Ojalvo, JordiSoriano Fradera, JordiRaya Chamorro, ÁngelConsiglio, Antonella2021-08-062021-08-062021Carola 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/s41531-021-00198-32373-8057http://hdl.handle.net/10230/48322A 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.application/pdfeng© 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/.Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegenerationinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41531-021-00198-3Diseases of the nervous systemNeuroscienceinfo:eu-repo/semantics/openAccess