Low-dose bafilomycin attenuates neuronal cell death associated with autophagy-lysosome pathway dysfunction

• Published in: Journal of neurochemistry 2010-08, Vol.114 (4), p.1193-1204
• Main Authors: Pivtoraiko, Violetta N, Harrington, Adam J, Mader, Burton J, Luker, Austin M, Caldwell, Guy A, Caldwell, Kim A, Roth, Kevin A, Shacka, John J
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; autophagy; Autophagy - drug effects; Autophagy - physiology; bafilomycin; Biochemistry; Biological and medical sciences; Caenorhabditis elegans - drug effects; cathepsin D; Cell Line, Tumor; Cellular biology; Cytoprotection - drug effects; Cytoprotection - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Humans; lysosome; Lysosomes - drug effects; Lysosomes - physiology; Macrolides - pharmacology; Medical sciences; Nerve Degeneration - drug therapy; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Parkinson disease; Parkinson’s Disease; Signal Transduction - drug effects; Tumors of the nervous system. Phacomatoses; α-synuclein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06838.x

J. Neurochem. (2010) 114, 1193-1204. We have shown previously that the plecomacrolide antibiotics bafilomycin A1 and B1 significantly attenuate cerebellar granule neuron death resulting from agents that disrupt lysosome function. To further characterize bafilomycin-mediated cytoprotection, we examined its ability to attenuate the death of naïve and differentiated neuronal SH-SY5Y human neuroblastoma cells from agents that induce lysosome dysfunction in vitro, and from in vivo dopaminergic neuron death in C. elegans. Low-dose bafilomycin significantly attenuated SH-SY5Y cell death resulting from treatment with chloroquine, hydroxychloroquine amodiaquine and staurosporine. Bafilomycin also attenuated the chloroquine-induced reduction in processing of cathepsin D, the principal lysosomal aspartic acid protease, to its mature 'active' form. Chloroquine induced autophagic vacuole accumulation and inhibited autophagic flux, effects that were attenuated upon treatment with bafilomycin and were associated with a significant decrease in chloroquine-induced accumulation of detergent-insoluble α-synuclein oligomers. In addition, bafilomycin significantly and dose-dependently attenuated dopaminergic neuron death in C. elegans resulting from in vivo over-expression of human wild-type α-synuclein. Together, our findings suggest that low-dose bafilomycin is cytoprotective in part through its maintenance of the autophagy-lysosome pathway, and underscores its therapeutic potential for treating Parkinson's disease and other neurodegenerative diseases that exhibit disruption of protein degradation pathways and accumulation of toxic protein species.