Binding of neuronal α-synuclein to β-III tubulin and accumulation in a model of multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative disease caused by α-synuclein (α-syn) accumulation in oligodendrocytes and neurons. We generated a transgenic (Tg) mouse model in which human α-syn was overexpressed in oligodendrocytes. Our previous studies have revealed that oligodendrocytic α-syn inclusions induced neuronal α-syn accumulation, thereby resulting in progressive neuronal degeneration in mice. We also demonstrated that an insoluble complex of α-syn and β-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 α-syn to β-III tubulin and not from α-syn self-aggregation. Thus, interaction between α-syn and β-III tubulin plays an important role in neuronal α-syn accumulation in an MSA mouse model.

► Binding of α-synuclein to β-III tubulin causes neuronal degeneration in MSA model.
► α-Synuclein interacted with β-III tubulin and formed an insoluble protein complex.
► Rifampicin reduces α-synuclein self-aggregation in GCI formation.
► Suppression of microtubule polymerization prevents neuronal α-synuclein accumulation.
► Microtubule depolymerization repressed the accumulation by binding to β-III tubulin.