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Biol Pharm Bull. 2011;34(7):1078-83.

α-Synuclein aggregation and transmission are enhanced by leucine-rich repeat kinase 2 in human neuroblastoma SH-SY5Y cells.

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National Institute of Health Sciences, Division of Novel Foods and Immunochemistry, 1–18–1 Kamiyoga, Setagaya-ku, Tokyo 158–8501, Japan.


Formation of α-synuclein aggregates is a key step in Parkinson's disease pathogenesis although the etiology remains elusive. α-Synuclein is accumulated in degenerating neurons, leading to the production of filamentous inclusions such as Lewy bodies. However, the in vitro overexpression of α-synuclein alone failed to induce inclusion bodies consisting of phosphorylated α-synuclein. The seeded aggregates-initiated polymerization of α-synuclein and tau has been reported elsewhere. What molecule is an initiator of filamentous inclusions remains to be defined. Here, we report that leucine-rich repeat kinase 2 (LRRK2)-cotransfection together with α-synuclein enhance the aggregate formation, phosphorylation, release to extracellular media of α-synuclein, and the cell-to-cell transmission into neighboring cells in human neuroblastoma SH-SY5Y cells. In cells transfected with α-synuclein alone, the proteins were distributed in the cytosol and did not form inclusions. On the other hand, the inclusions and phosphorylation of α-synuclein were formed in cells cotransfected with α-synuclein and LRRK2 G2019S mutant together. LRRK2 G2019S-cotransfected PC12 cells also induced the aggregates. Furthermore, the cell-to-cell transmission of α-synuclein and the cell toxicity were also enhanced by either LRRK2 wild type or G2019S mutant, whereas the cell viability was not decreased in cells transfected with α-synuclein alone. These results suggest that overexpression of LRRK2, especially G2019S mutant, whose functions remain unclear, initiate the aggregate formation, release and transmission of α-synuclein, resulting in the propagation of α-synuclein to neighboring cells and reduction of cell viability.

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