Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans.
Necrotic cell death is a common feature in numerous human neurodegenerative disorders. In the nematode Caenorhabditis elegans, gain-of-function mutations in genes that encode specific ion channel subunits such as the degenerins DEG-1 and MEC-4, and the acetylcholine receptor subunit DEG-3 lead to necrotic-like degeneration of a subset of neurons. Neuronal demise caused by ion channel hyperactivity is accompanied by intense degradation of cytoplasmic contents, dramatic membrane infolding and vacuole formation; however, the cellular pathways underlying such processes remain largely unknown. Here we show that the function of three autophagy genes, whose yeast and mammalian orthologs are implicated in cytoplasmic self-degradation, membrane trafficking and the cellular response to starvation, contributes to ion-channel-dependent neurotoxicity in C. elegans. Inactivation of unc-51, bec-1 and lgg-1, the worm counterparts of the yeast autophagy genes Atg1, Atg6 and Atg8 respectively, partially suppresses degeneration of neurons with toxic ion channel variants. We also demonstrate that the TOR-kinase-mediated signaling pathway, a nutrient sensing system that downregulates the autophagy gene cascade, protects neurons from undergoing necrotic cell death, whereas nutrient deprivation promotes necrosis. Our findings reveal a role for autophagy genes in neuronal cell loss in C. elegans.
Tóth
Márton L
ML
Department of Genetics, Eötvös Loránd University, Budapest, H-1117, Hungary.
Simon
Péter
P
Kovács
Attila L
AL
Vellai
Tibor
T
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D009154:Mutation; D009336:Necrosis / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D033921:Vesicular Transport Proteins
D018663:Adrenergic Agents; D029742:Caenorhabditis elegans Proteins; D007473:Ion Channels; C115871:Mec-4 protein, C elegans; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C477268:bec-1 protein, C elegans; D016627:Oxidopamine; D017853:Phosphotransferases (Alcohol Group Acceptor); C112443:UNC-51 protein, C elegans; C472494:let-363 protein, C elegans; D017346:Protein Serine-Threonine Kinases