Multiple system atrophy (MSA) is a neurodegenerative disease caused by alpha-synuclein (alpha-syn) accumulation in oligodendrocytes and neurons. We generated a transgenic (Tg) mouse model in which human alpha-syn was overexpressed in oligodendrocytes. Our previous studies have revealed that oligodendrocytic alpha-syn inclusions induced neuronal alpha-syn accumulation, thereby resulting in progressive neuronal degeneration in mice. We also demonstrated that an insoluble complex of alpha-syn and beta-III tubulin in microtubules progressively accumulated in neurons, thereby leading to neuronal degeneration. In the present study, we demonstrated that neuronal accumulation of the insoluble complex was derived from binding of alpha-syn to beta-III tubulin and not from alpha-syn self-aggregation. Thus, interaction between alpha-syn and beta-III tubulin plays an important role in neuronal alpha-syn accumulation in an MSA mouse model. (C) 2011 Elsevier Inc. All rights reserved.