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The Journal of Neuroscience, April 15, 1998, 18(8):2871-2880

G_s-Induced Neurodegeneration in Caenorhabditis elegans

Allison J. Berger, Anne C. Hart, and Joshua M. Kaplan

Department of Genetics, Harvard Medical School, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114

We describe a genetic model for neurodegeneration in the nematode Caenorhabditis elegans. Constitutive activation of the GTP-binding protein G_s 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 G_s-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent G_s-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against G_s-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, G_s-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 G_s. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.

Key words: cell death; neurodegeneration; necrosis; signal transduction; G-protein; cAMP; mutant; Caenorhabditis elegans

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1882871-10$05.00/0

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