Journal Article

Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

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

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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 / Mitochondria / Molecular modelling / Movement disorders / Mutation / Neurodegenerative diseases / Neurotoxicity / Oxygen / Parkinson's disease / Pathogenesis / Pathology / Penicillin / Propagation / Protein Multimerization / Protein Transport / Proteins / Rats / Reactive oxygen species / Reactive Oxygen Species - metabolism / Rupturing / Synuclein / Toxicity / Viruses