Mesenchymal stem cells modulate misfolded alpha-synuclein in parkinsonian disorders: A multitarget disease-modifying strategy

Abstract

alpha-Synuclein (alpha-Syn) aggregates, the major toxic component of Lewy bodies, are proteinaceous fibrillar cytoplasmic inclusions observed in alpha-synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Overexpression of alpha-syn induce neuronal loss and alpha-syn aggregation in PD animals. Recent studies show that alpha-syn is released by exocytosis and can be transmitted between brain areas through cell-to-cell propagation. Moreover, aggregates of extracellular alpha-syn can induce neuroinflammation-mediated neurotoxic signaling through microglial activation and release of pro-inflammatory factors. Thus, modulation of alpha-syn might be a potential therapeutic strategy for modifying disease progression of alpha-synucleinopathies. Our previous studies have revealed that MSCs have potent neuroprotective effects in PD animal through modulation of neuroinflammation, inhibition of cell death, and promotion of neurogenesis. Here, we provide further evidence that MSCs have the potential to modulate alpha-syn-related microenvironments via enhancement of autophagy, proteolysis of alpha-syn aggregates, inhibition of cell-to-cell transmission of alpha-syn, stabilization of axonal transport, and phagocytic clearance of alpha-syn by microglial M2 polarization. With advantages in clinical applications, these data suggests that the use of MSCs as pharmacological modulators of alpha-syn propagation would be an effective therapeutic approach in PD.