Gαs-Induced Neurodegeneration inCaenorhabditis elegans

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Abstract
We describe a genetic model for neurodegeneration in the nematodeCaenorhabditis elegans. Constitutive activation of the GTP-binding protein Gαsinduces 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 Gαs-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent Gαs-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against Gαs-induced cell deaths. Theacy-1gene 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 theunc-36andeat-4genes are partially neuroprotective, which indicates that endogenous signaling modulates the severity of the neurotoxic effects of Gαs. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.