title: α-Synuclein aggregation and transmission are enhanced by leucine-rich repeat kinase 2 in human neuroblastoma SH-SY5Y cells.
abstract: 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.
authors: National Institute of Health Sciences, Division of Novel Foods and Immunochemistry, 1–18–1 Kamiyoga, Setagaya-ku, Tokyo 158–8501, Japan. kondo@nihs.go.jp
authors: Kazunari
authors: K
authors: Kondo
authors: Saemi
authors: S
authors: Obitsu
authors: Reiko
authors: R
authors: Teshima
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases