Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the abnormal accumulation of toxic forms of the synaptic protein alpha-synuclein (α-syn) within oligodendrocytes and neurons. The presence of α-syn within oligodendrocytes in the form of glial cytoplasmic inclusions is the diagnostic hallmark of MSA. However, it has been postulated that α-syn is produced in neurons and propagates to oligodendrocytes, where unknown mechanisms lead to its accumulation. The presence of α-syn within neurons in MSA has not been so extensively studied, but it may shed light into neuropathological mechanisms leading to oligodendroglial accumulation. Here we summarize the principal neuropathological events of MSA, and discuss how a deeper knowledge of these mechanisms may help develop effective therapies targeting α-syn accumulation and spreading.