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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 Gs-induced cytotoxicity, ranging from
0 to 88% of cells affected. Mutations that prevent programmed cell
death do not prevent Gs-induced killing, suggesting that
these deaths do not occur by apoptosis. Mutations in three genes
protect against Gs-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 Gs.
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
Copyright © 1998 Society for Neuroscience 0270-6474/98/1882871-10$05.00/0
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