Autophagy, Bafilomycin and Cell Death: The "A-B-Cs" of Plecomacrolide-Induced Neuroprotection

• Published in: Autophagy Vol. 2; no. 3; pp. 228 - 230
• Main Authors: Shacka, John J., Klocke, Barbara J., Roth, Kevin A.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.07.2006
• Subjects: Animals; Apoptosis - drug effects; Autophagy - drug effects; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cycle; Landes; Macrolides - pharmacology; Neuroprotective Agents - pharmacology; Organogenesis; Proteins
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.2703

Bafilomycin A1 (BafA1), which is a member of the plecomacrolide sub-class of macrolide antibiotics, has differential, concentration-dependent effects on neuronal cell viability. When used at high concentrations, BafA1 inhibits vacuolar ATPase (V-ATPase), promotes the accumulation of autophagic vacuoles and triggers Bax-dependent apoptosis. These effects are similar to those induced by the lysosomotropic agent chloroquine. Conversely, at concentrations below its reported ability to completely inhibit V-ATPase, BafA1 dramatically attenuates chloroquine-induced apoptosis. The protective effects of BafA1 appear to be independent of the chloroquine-induced accumulation of autophagosomes. Rather, BafA1 appears to inhibit events downstream of chloroquine-induced autophagosome accumulation, such as the loss mitochondrial or lysosomal integrity. Our finding that BafA1 inhibits the death of neurons induced by autophagic stress suggests a potentially novel mechanism of action apart from its ability to inhibit V-ATPase. Here we provide further evidence of neuroprotection against chloroquine-induced death by plecomacrolide antibiotics that are structurally similar to BafA1, including bafilomycin B1 and concanamycin A, and discuss potential mechanism(s) of neuroprotection against autophagic stress. Addendum to: Bafilomycin A1 Inhibits Chloroquine-Induced Death of Cerebellar Granule Neurons John J. Shacka, Barbara J. Klocke, Masahiro Shibata, Yasuo Uchiyama, Geeta Datta, Robert E. Schmidt and Kevin A. Roth Mol Pharmacol 2006; 69:1125-36