Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

Abstract

Alpha-synuclein (aSyn) aggregation within mature oligodendrocytes is the characteristic neuropathological feature of multiple system atrophy (MSA). In fact, dysfunction of oligodendrocytes is considered as a primary event in MSA pathogenesis leading to myelin loss and, ultimately, reduced axonal integrity and neuronal cell loss. Oligodendrocyte progenitor cells (OPCs) are widely distributed in the adult central nervous system and represent a potential endogenous source for replacement of such dysfunctional oligodendrocytes. The extent to which OPCs are affected in MSA or even contribute to MSA pathogenesis remains undefined. Thus, we analyzed OPCs post-mortem in MSA brains and in a pre-clinical MSA mouse model expressing aSyn under the myelin basic protein (MBP) promoter. Importantly, we detected elevated numbers of striatal OPCs in MSA and its model 1 . Observing aSyn-positive OPCs in MSA patients, we additionally established two independent in vitro models in order to explore the effect of intracellular aSyn on OPC maturation. Both stable aSyn expressing OPC-like central glia-4 (CG4) cells 1 and transiently aSyn expressing primary OPCs derived from neonatal rats 2 robustly showed a severely reduced maturation. Similarly, primary OPCs exhibit a delayed maturation upon uptake of recombinant aSyn 2 . Taken together, our findings indicate that OPC dysfunction is a pathological feature of MSA. In addition, promoting OPC differentiation may represent a novel and promising interventional strategy for therapeutic approaches in MSA.