Microtubule depolymerization suppresses α-synuclein accumulation in a mouse model of multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease caused by an accumulation of a-synuclein (α- syn) in oligodendrocytes. Little is known about the cellular mechanisms by which α-syn accumulation causes neuronal degeneration in MSA. Our previous research, however, revealed that in a mouse model of MSA, oligodendrocytic inclusions of α-syn induced neuronal accumulation of α-syn, as well as progressive neuronal degeneration. Here we identify the mechanisms that underlie neuronal accumulation of α-syn in a mouse MSA model. We found that the α-syn protein binds to β-III tubulin in microtubules to form an insoluble complex. The insoluble α-syn complex progressively accumulates in neurons and leads to neuronal dysfunction. Furthermore, we demonstrated that the neuronal accumulation of insoluble α-syn is suppressed by treatment with a microtubule depolymerizing agent. The underlying pathological process appeared to also be inhibited by this treatment, providing promise for future therapeutic approaches. © American Society for Investigative Pathology.