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

• DOI: 10.1038/s41531-021-00198-3
• Publication Date: 2021-07-02T10:04:19Z
• Authors: 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
• Keywords: LRRK2; Neurite

Abstract A deeper understanding of early disease mechanisms occurring in Parkinson’s (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 functional maturation over time. Compared control neuronal networks, PD patients’ displayed an elevated bursting behavior, the absence neurodegeneration. By combining calcium imaging, biophysical modeling, and DAn-lineage tracing, found a decrease DAn neurite density triggered overall alterations networks. Our data implicate dysfunction as prime focus may contribute initiation downstream degenerative pathways preceding loss PD, highlighting potential window opportunity for pre-symptomatic assessment chronic diseases.