G alphas-induced neurodegeneration in Caenorhabditis elegans.
We describe a genetic model for neurodegeneration in the nematode Caenorhabditis elegans. Constitutive activation of the GTP-binding protein Galphas induces neurodegeneration. Neuron loss occurs in two phases whereby affected cells undergo a swelling response in young larvae and subsequently die sometime during larval development. Different neural cell types vary greatly in their susceptibility to Galphas-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent Galphas-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against Galphas-induced cell deaths. The acy-1 gene is absolutely required for neurodegeneration, and the predicted ACY-1 protein is highly similar (40% identical) to mammalian adenylyl cyclases. Thus, Gs-induced neurodegeneration is mediated by the second messenger cAMP. Mutations in the unc-36 and eat-4 genes are partially neuroprotective, which indicates that endogenous signaling modulates the severity of the neurotoxic effects of Galphas. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.
Berger
A J
AJ
Department of Genetics, Harvard Medical School, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Hart
A C
AC
Kaplan
J M
JM
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D000242:Cyclic AMP / Q000378:metabolism; D004924:Escape Reaction / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D009336:Necrosis; D009410:Nerve Degeneration / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; C469573:ACY-1 protein, C elegans; D000262:Adenylyl Cyclases