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

Carola, Giulia; Malagarriga, Daniel; Calatayud, Carles; Pons Espinal, Meritxell, 1986-; Blasco Agell, Lucas; Richaud Patin, Yvonne; Fernández Carasa, Irene; Baruffi, Valentina; Beltramone, Santiago; Molina, Emilio; Dell'Era, Patrizia; Toledo Aral, Juan J.; Tolosa, Eduard; Muotri, Alysson R.; García Ojalvo, Jordi; Soriano Fradera, Jordi; Raya Chamorro, Ángel; Consiglio, Antonella

doi:http://dx.doi.org/10.1038/s41531-021-00198-3

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

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

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.