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s41531-021-00198-3.pdf (7.85 MB)

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2021-07-02

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cc by (c) Carola, Giulia et al., 2021
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/179150

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

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https://doi.org/10.1038/s41531-021-00198-3

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.

Subject

Malaltia de Parkinson, Mutació (Biologia), Enginyeria genètica

Subject (English)

Parkinson's disease, Mutation (Biology), Genetic engineering

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Física de la Matèria Condensada)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Institut de Recerca en Sistemes Complexos (UBICS))

Citation

CAROLA, Giulia, et al. Parkinson’s disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration. npj Parkinson's Disease. 2021. Vol. 7, num. 55. ISSN 2373-8057. [consulted: 14 of August of 2026]. Available at: https://hdl.handle.net/2445/179150

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