Myelin loss is a widespread neuropathological hallmark of the atypical parkinsonian disorder multiple system atrophy (MSA). On a cellular level, MSA is characterized by alpha-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCIs) within mature oligodendrocytes leading to demyelination as well as axonal and neuronal loss. Oligodendrocyte progenitor cells (OPCs) represent a proliferative cell population distributed throughout the adult mammalian central nervous system. During remyelination, OPCs are recruited to sites of demyelination, differentiate, and finally replace dysfunctional mature oligodendrocytes. However, comprehensive studies investigating OPCs and remyelination processes in MSA are lacking. In the present study, we therefore investigate the effect of human aSyn (h-aSyn) on early primary rat OPC maturation. Upon lentiviral transduction, h-aSyn expressing OPCs exhibit fewer and shorter primary processes at the initiation of differentiation. Until day 4 of a 6 day differentiation paradigm, h-aSyn expressing OPCs further show a severely delayed maturation evidenced by reduced myelin gene expression and increased levels of the progenitor marker platelet derived growth factor receptor-alpha (PDGFRα). Matching these results, OPCs that take up extracellular recombinant h-aSyn exhibit a similar delayed differentiation. In both experimental setups however, myelin gene expression is restored at day 6 of differentiation paralleled by decreased intracellular h-aSyn levels indicating a reverse correlation of h-aSyn and the differentiation potential of OPCs. Taken together, these findings suggest a tight link between the intracellular level of h-aSyn and maturation capacity of primary OPCs.