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Bafilomycin A1 protects against autophagic stress‐induced neuron death
Author(s) -
Shacka John Joseph,
Klocke Barbara J,
Roth Kevin A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1175-c
Subject(s) - autophagy , programmed cell death , calpain , bafilomycin , microbiology and biotechnology , neuron , apoptosis , chemistry , lysosome , western blot , pharmacology , biology , biochemistry , neuroscience , enzyme , gene
Autophagy is the homeostatic degradation and recycling of macronutrients and organelles mediated by their targeted delivery to lysosomes. Autophagic stress occurs with nutrient deprivation or lysosome dysfunction and if left unchecked can lead to both caspase‐dependent and –independent cell death. We have shown previously that treatment with the lysosomotropic agent chloroquine (CQ) induces autophagic stress and subsequent neuron death that is inhibited by targeted Bax deletion, and that the plecomacrolide antibiotic bafilomycin A1 (BafA1) dramatically attenuates CQ‐induced neuron death. To further delineate the role of Bax in autophagic stress‐induced death, Bax levels were measured by western blot analysis in lysates of cerebellar granule neurons following treatment with CQ. A slight decrease in full length Bax was observed at 16h and 24h following CQ treatment. An 18 kDa Bax cleavage product (p18 Bax), shown previously to represent a specific calpain cleavage product that accelerates the rate of apoptosis, appeared at 16h following CQ treatment and remained prominent at 24h. Treatment with 1 nM BafA1 in the presence of CQ caused a near complete attenuation in levels of p18 Bax, concomitant with a reduction in caspase‐3 activity and attenuation of neuron death. Together these data support a novel neuroprotective mechanism of BafA1 that may involve attenuation of calpain‐induced neuron death.