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.

NPJ Parkinson's disease (2021-07-04)

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

PMID34215735

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.

MATERIALS

Product Number

Brand

Product Description

E5134

Sigma-Aldrich

Ethylenediaminetetraacetic acid disodium salt dihydrate, suitable for electrophoresis, for molecular biology, 99.0-101.0% (titration)

565770

Sigma-Aldrich

γ-Secretase Inhibitor IX, Gamma-Secretase Inhibitor IX - CAS 208255-80-5, is a cell-permeable inhibitor of γ-secretase (Aβtotal IC₅₀ = 115 nM, Aβ42 IC₅₀ = 200 nM).

540220

Sigma-Aldrich

Purmorphamine, A cell-permeable activator of Hedgehog signaling that induces osteoblast differentiation of multipotent mesenchymal progenitor cells C3H10T1/2 (EC₅₀ = 1 µM).