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Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis Journal Article
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| Authors: | Freeman, D.; Cedillos, R.; Choyke, S.; Lukic, Z.; McGuire, K.; Marvin, S.; Burrage, A. M.; Sudholt, S.; Rana, A.; O'Connor, C; Wiethoff, C. M.; Campbell, E. M. |
| Article Title: | Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis |
| Abstract: | alpha-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that alpha-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that alpha-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of alpha-synuclein aggregates directly into cells as well as by cell-to-cell transfer of alpha-synuclein. We also observe that lysosomal rupture by alpha-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that alpha-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of alpha-synuclein pathology in cells. |
| Journal Title: | PloS one |
| Volume: | 8 |
| Issue: | 4 |
| ISSN: | 1932-6203; 1932-6203 |
| Publisher: | Unknown |
| Journal Place: | United States |
| Date Published: | 2013 |
| Start Page: | e62143 |
| Language: | eng |
| DOI/URL: | |
| Notes: | ID: 12892; JID: 101285081; OID: NLM: PMC3636263; 2013 [ppublish]; 2012/12/14 [received]; 2013/03/18 [accepted]; 2013/04/25 [epublish]; epublish |
