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Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis

Freeman, David ; Cedillos, Rudy ; Choyke, Samantha ; Lukic, Zana ; McGuire, Kathleen ; Marvin, Shauna ; Burrage, Andrew M ; Sudholt, Stacey ; Rana, Ajay ; O'Connor, Christopher ; Wiethoff, Christopher M ; Campbell, Edward M Kahle, Philipp J.

PloS one, 2013-04, Vol.8 (4), p.e62143-e62143 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis
Autor: Freeman, David ; Cedillos, Rudy ; Choyke, Samantha ; Lukic, Zana ; McGuire, Kathleen ; Marvin, Shauna ; Burrage, Andrew M ; Sudholt, Stacey ; Rana, Ajay ; O'Connor, Christopher ; Wiethoff, Christopher M ; Campbell, Edward M
Kahle, Philipp J.
Assuntos: Adenoviruses ; Aggregates ; alpha-Synuclein - chemistry ; alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; alpha-Synuclein - pharmacology ; Animals ; Bacteria ; Biochemistry ; Biology ; Cathepsin B ; Cathepsins ; Cathepsins - metabolism ; Cell culture ; Cell Line, Tumor ; Cell lines ; Cytokines ; Cytotoxicity ; Endocytosis ; Endocytosis - drug effects ; Growth factors ; Humans ; Immunology ; Inflammasomes ; Inflammasomes - metabolism ; Lysosomes ; Lysosomes - drug effects ; Lysosomes - metabolism ; Medical research ; Medicine ; Medicine, Experimental ; Mitochondria ; Molecular modelling ; Movement disorders ; Mutation ; Neurodegenerative diseases ; Neurotoxicity ; Oxygen ; Parkinson's disease ; Parkinsons disease ; Pathogenesis ; Pathology ; Penicillin ; Propagation ; Protein Multimerization ; Protein Transport ; Proteins ; Rats ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rupturing ; Synuclein ; Toxicity ; Viruses
É parte de: PloS one, 2013-04, Vol.8 (4), p.e62143-e62143
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SourceType-Scholarly Journals-1
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content type line 23
Conceived and designed the experiments: DF RC KM SM AB CW EC. Performed the experiments: DF RC SC SS CO ZL. Analyzed the data: DF RC SC SS CO ZL. Contributed reagents/materials/analysis tools: SC SS AB AR. Wrote the paper: DF EC.
Competing Interests: The authors have declared that no competing interests exist.
Descrição: α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-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 α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of α-synuclein aggregates directly into cells as well as by cell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that α-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 α-synuclein pathology in cells.
Editor: United States: Public Library of Science
Idioma: Inglês

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Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis

Freeman, David ; Cedillos, Rudy ; Choyke, Samantha ; Lukic, Zana ; McGuire, Kathleen ; Marvin, Shauna ; Burrage, Andrew M ; Sudholt, Stacey ; Rana, Ajay ; O'Connor, Christopher ; Wiethoff, Christopher M ; Campbell, Edward M Kahle, Philipp J.

United States: Public Library of Science

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