title: Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution.
abstract: Autophagy is a mechanism whereby cells digest themselves from within and so may be used in lieu of apoptosis to execute cell death. Little is known about its role in neurons. In newly isolated sympathetic neurons, two independent apoptotic stimuli, NGF-deprivation or cytosine arabinoside added in the presence of NGF, caused a 30-fold increase in autophagic particle numbers, many autophagosomes appearing before any signs of DNA-fragmentation. The anti-autophagic drug 3-methyladenine also delayed apoptosis, its neuroprotection correlating with inhibition of cytochrome c release from mitochondria and prevention of caspase activation. In contrast, autophagic activity remained elevated in neurons treated with the pan-caspase inhibitor Boc-Asp(OMe)fmk, which inhibited morphological apoptosis but did not inhibit cytochrome c release nor prevent cell death. We propose that the same apoptotic signals that cause mitochondrial dysfunction also activate autophagy. Once activated, autophagy may mediate caspase-independent neuronal death.
authors.affiliation: Department of Biochemistry, University of Cambridge, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Xue
authors.forename: G C
authors.initials: GC
authors.lastname: Fletcher
authors.forename: A M
authors.initials: AM
authors.lastname: Tolkovsky
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology* / Q000502:physiology
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C025946:3-methyladenine; D000225:Adenine