iPSC-Derived Striatal Medium Spiny Neurons from Patients with Multiple System Atrophy Show Hypoexcitability and Elevated α-Synuclein Release


Multiple system atrophy of the parkinsonian type (MSA-P) is a rare, fatal neurodegenerative disease with sporadic onset. It is still unknown if MSA-P is a primary oligodendropathy or caused by neuronal pathophysiology leading to severe, α-synuclein-associated neurodegeneration, mainly in the striatum. In this study, we generated and differentiated induced pluripotent stem cells (iPSCs) from patients with the clinical diagnosis of probable MSA-P (n = 3) and from three matched healthy controls into GABAergic striatal medium spiny neurons (MSNs). We found a significantly elevated release and neuronal distribution for α-synuclein, as well as hypoexcitability in the MSNs derived from the MSA-P patients compared to the healthy controls. These data suggest that the striatal hypoexcitable neurons of MSA-P patients contribute to a pathological α-synuclein burden which is likely to spread to neighboring cells and projection targets, facilitating disease progression.

Authors Henkel LM, Kankowski S, Moellenkamp TM, Smandzich NJ, Schwarz S, Di Fonzo A, Göhring G, Höglinger G, Wegner F
Journal Cells
Publication Date 2023 Jan 4;12(2)
PubMed 36672158
PubMed Central PMC9856678
DOI 10.3390/cells12020223

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