Accelerated α-synuclein aggregation after differentiation of SH-SY5Y neuroblastoma cells

alpha-Synticlein (alpha-syn) is a major component of inclusion bodies in Parkinson's disease (PD) and other synucleinopathies. To clarify the possible roles of a-syn in the molecular pathogenesis of neurodegenerative diseases, we have established a novel cellular model based on the differentiation of SH-SY5Y cells that overexpress alpha-syn. In the presence of ferrous iron, differentiation of the cells led to the formation of large perinuclear inclusion bodies, which developed from scattered small aggregates seen in undifferentiated cells. The iron-induced alpha-synpositive inclusions co-localized largely with ubiquitin, and some of them were positive for nitrotyrosine, lipid, gamma-tubulin and dynein. Notably, treatment with nocodazole, a microtubule depolymerizing agent, interrupted the aggregate formation but led to a concomitant increase of apoptotic cells. Therefore, it appears that an intracellular retrograde transport system via inicrotubules plays a crucial role in the aggregate formation and also that the aggregates may represent a cytoprotective response against noxious stimuli. This cellular model will enable better understanding of the molecular pathomechanisms of synucleinopathy. (C) 2004 Elsevier B.V. All rights reserved.