Multiple system atrophy (MSA) is a sporadic, adult-onset neurodegenerative disease, which is characterized by striatonigral degeneration, olivopontocerebellar atrophy, and preganglionic autonomic lesions in any combination. The histological hallmark is the presence of argyrophilic fibrillary inclusions in the oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Fibrillary inclusions are also found in the neuronal somata, axons, and nucleus. Neuronal cytoplasmic inclusions are frequently found in the pontine and inferior olivary nuclei. Since the discovery of α-synuclein as a major component of glial and neuronal inclusions in MSA, two neurodegenerative processes have been considered in this disease: one is due to the widespread occurrence of GCIs associated with oligodendroglia–myelin degeneration (oligodendrogliopathy) in the central nervous system, and the other is due to the filamentous aggregation of α-synuclein in the neurons in several brain regions. These two degenerative processes might synergistically cause neuronal depletion in MSA.