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

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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Autores principales: 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
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2021
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Neurology. Diseases of the nervous system
RC346-429
Acceso en línea:https://doaj.org/article/7c8c8c544c2b4347a40c5da25a5f23b4
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spelling oai:doaj.org-article:7c8c8c544c2b4347a40c5da25a5f23b42021-12-02T18:18:52ZParkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration10.1038/s41531-021-00198-32373-8057https://doaj.org/article/7c8c8c544c2b4347a40c5da25a5f23b42021-07-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00198-3https://doaj.org/toc/2373-8057Abstract 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.G. CarolaD. MalagarrigaC. CalatayudM. Pons-EspinalL. Blasco-AgellY. Richaud-PatinI. Fernandez-CarasaV. BaruffiS. BeltramoneE. MolinaP. Dell’EraJ. J. Toledo-AralE. TolosaA. R. MuotriJ. Garcia OjalvoJ. SorianoA. RayaA. ConsiglioNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-14 (2021)
institution DOAJ
collection DOAJ
language EN
topic Neurology. Diseases of the nervous system
RC346-429
spellingShingle Neurology. Diseases of the nervous system
RC346-429
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
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.
format article
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
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 Portfolio
publishDate 2021
url https://doaj.org/article/7c8c8c544c2b4347a40c5da25a5f23b4
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