Mesenchymal stem cells inhibit transmission of α-synuclein by modulating clathrin-mediated endocytosis in parkinsonian models

Abstract

Ample evidence has suggested that misfolded α-synuclein can be released from cells and transmitted from one brain area to others through cell-to-cell propagation in Parkinson’s disease (PD). In terms of prion-like behavior, extracellular α-synuclein plays key roles in the pathogenesis and progression of α-synucleinopathies. Mesenchymal stem cells (MSCs) secrete various cytotropic factors that have neuroprotective effects through complex mechanisms, such as modulation of neuroinflammation, enhancement of cell survival signals, increased neurogenesis, and modulation of autophagy. In the present study, we investigated whether MSCs could exert neuroprotective effects through modulation of cell-to-cell transmission on extracellular α-synuclein. Using α-synuclein-enriched models, we showed that mesenchymal stem cells (MSCs) inhibited cell-to-cell transmission by blocking the clathrin-mediated endocytosis of extracellular α-synuclein via modulation of the interaction with N-methyl-D-aspartate receptors, which led to a prosurvival effect on neurons with functional improvement of motor deficits. Moreover, MSC treatment significantly inhibited transmission of α-synuclein from ipsilateral to contralateral hemisphere of α-synuclein inoculation compared to α-synuclein treated PD animals. Furthermore, Galectin-1, soluble factors derived from MSCs, played an important role in the transmission control of extracellular α-synuclein in these models. Our data suggest that MSCs exert neuroprotective properties through inhibition of cell-to-cell transmission of extracellular α-synuclein, which may be applicable to clinical strategies for treatment of PD patients.