Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration
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 P...
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2021-07-01
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Series: | npj Parkinson's Disease |
Online Access: | https://doi.org/10.1038/s41531-021-00198-3 |
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doaj-7c8c8c544c2b4347a40c5da25a5f23b42021-07-04T11:33:56ZengNature Publishing Groupnpj Parkinson's Disease2373-80572021-07-017111410.1038/s41531-021-00198-3Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegenerationG. Carola0D. Malagarriga1C. Calatayud2M. Pons-Espinal3L. Blasco-Agell4Y. Richaud-Patin5I. Fernandez-Carasa6V. Baruffi7S. Beltramone8E. Molina9P. Dell’Era10J. J. Toledo-Aral11E. Tolosa12A. R. Muotri13J. Garcia Ojalvo14J. Soriano15A. Raya16A. Consiglio17Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLRegenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), Hospital Duran i ReynalsDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLSanford Consortium for Regenerative Medicine, UC San DiegoCellular Fate Reprogramming Unit, Department of Molecular and Translational Medicine, University of BresciaInstituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaDepartment of Neurology, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB)Departments of Pediatrics and Cellular & Molecular Medicine, University of California San DiegoDepartment of Experimental and Health Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaDepartament de Física de la Matèria Condensada, Universitat de BarcelonaRegenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), Hospital Duran i ReynalsDepartment of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELLAbstract 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.https://doi.org/10.1038/s41531-021-00198-3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
G. Carola D. Malagarriga C. Calatayud M. Pons-Espinal L. Blasco-Agell Y. Richaud-Patin I. Fernandez-Carasa V. Baruffi S. Beltramone E. Molina P. Dell’Era J. J. Toledo-Aral E. Tolosa A. R. Muotri J. Garcia Ojalvo J. Soriano A. Raya A. Consiglio |
spellingShingle |
G. Carola D. Malagarriga C. Calatayud M. Pons-Espinal L. Blasco-Agell Y. Richaud-Patin I. Fernandez-Carasa V. Baruffi S. Beltramone E. Molina P. Dell’Era J. J. Toledo-Aral E. Tolosa A. R. Muotri J. Garcia Ojalvo J. Soriano A. Raya A. Consiglio Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration npj Parkinson's Disease |
author_facet |
G. Carola D. Malagarriga C. Calatayud M. Pons-Espinal L. Blasco-Agell Y. Richaud-Patin I. Fernandez-Carasa V. Baruffi S. Beltramone E. Molina P. Dell’Era J. J. Toledo-Aral E. Tolosa A. R. Muotri J. Garcia Ojalvo J. Soriano A. Raya A. Consiglio |
author_sort |
G. Carola |
title |
Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration |
title_short |
Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration |
title_full |
Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration |
title_fullStr |
Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration |
title_full_unstemmed |
Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration |
title_sort |
parkinson’s disease patient-specific neuronal networks carrying the lrrk2 g2019s mutation unveil early functional alterations that predate neurodegeneration |
publisher |
Nature Publishing Group |
series |
npj Parkinson's Disease |
issn |
2373-8057 |
publishDate |
2021-07-01 |
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. |
url |
https://doi.org/10.1038/s41531-021-00198-3 |
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