Multiple system atrophy is a sporadic, progressive, neurodegenerative disease characterized by an oligodendroglial accumulation of alpha-synuclein (α-syn). The mechanisms underlying the oligodendroglial accumulation of α-syn in the brains of patients with multiple system atrophy have attracted a great deal of interest, given the primarily neuronal role reported for this protein. We examined the interactions between neuronal and oligodendroglial α-syn in the progeny of crosses between parental transgenic (tg) mouse lines that express α-syn either under the oligodendroglial-specific myelin-basic protein promoter (MBP1-hα-syn tg) or under the neuronal platelet-derived growth factor promoter (PDGF-hα-syn tg). Our results demonstrate that progeny from the cross [hα-syn double (dbl) tg mice] displayed a robust redistribution of α-syn accumulation, with a relocalization from a neuronal or a mixed neuronal/oligodendroglial α-syn expression to a more oligodendroglial pattern in both the neocortex and the basal ganglia that closely resembled the parental MBP-hα-syn tg line. The hα-syn dbl tg mice also displayed motor deficits, concomitant with reduced levels of tyrosine hydroxylase and augmented neuropathological alterations in the basal ganglia. These results suggest that the central nervous system milieu in the hα-syn dbl tg mice favors an oligodendroglial accumulation of α-syn. This model represents an important tool to examine the interactions between neuronal and oligodendrocytic α-syn in diseases such as multiple system atrophy.