Accelerated alpha-synuclein aggregation after differentiation of SH-SY5Y neuroblastoma cells.
Alpha-synuclein (alpha-syn) is a major component of inclusion bodies in Parkinson's disease (PD) and other synucleinopathies. To clarify the possible roles of alpha-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-syn-positive 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 microtubules 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.
Hasegawa
Takafumi
T
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Matsuzaki
Michiko
M
Takeda
Atsushi
A
Kikuchi
Akio
A
Akita
Hirotoshi
H
Perry
George
G
Smith
Mark A
MA
Itoyama
Yasuto
Y
D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein