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: Kazunari Kondo, Saemi Obitsu, Reiko Teshima
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 34 Issue 7 Pg. 1078-83 ( 2011) ISSN: 1347-5215 [Electronic] Japan
• PMID: 21720016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Protein Serine-Threonine Kinases

Topics

• Blotting, Western
• Cell Line, Tumor
• Humans
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Mitochondria (metabolism)
• Neuroblastoma (enzymology, metabolism, pathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• alpha-Synuclein (metabolism)