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Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans

Nature volume 419, pages 939–944 (2002)Cite this article

Abstract

Necrotic cell death underlies the pathology of numerous human neurodegenerative conditions1. In the nematode Caenorhabditis elegans, gain-of-function mutations in specific ion channel genes such as the degenerin genes deg-1 and mec-4, the acetylcholine receptor channel subunit gene deg-3 and the Gs protein α-subunit gene gsa-1 evoke an analogous pattern of degenerative (necrotic-like) cell death in neurons that express the mutant proteins2,3,4,5,6. An increase in concentrations of cytoplasmic calcium in dying cells, elicited either by extracellular calcium influx or by release of endoplasmic reticulum stores, is thought to comprise a major death-signalling event7,8. But the biochemical mechanisms by which calcium triggers cellular demise remain largely unknown. Here we report that neuronal degeneration inflicted by various genetic lesions in C. elegans requires the activity of the calcium-regulated CLP-1 and TRA-3 calpain proteases and aspartyl proteases ASP-3 and ASP-4. Our findings show that two distinct classes of proteases are involved in necrotic cell death and suggest that perturbation of intracellular concentrations of calcium may initiate neuronal degeneration by deregulating proteolysis. Similar proteases may mediate necrotic cell death in humans.

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Figure 1: Aspartyl protease deficiency suppresses neurodegeneration in C. elegans.
Figure 2: Specific aspartyl proteases are required for neurodegeneration in C. elegans.
Figure 3: Specific calpain proteases are required for neurodegeneration in C. elegans.
Figure 4: Calpains act sequentially with aspartyl proteases to facilitate cell death.

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Acknowledgements

We thank P. Kuwabara and S. Sokol for communicating results before publication; C. Samara for technical help; and colleagues for discussions and comments on the manuscript. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. Certain strains were from the NemaPharm Group of Axys Pharmaceuticals. We thank A. Fire for plasmid vectors and L. Jacobson for cad-1 mutant strains. This work was funded in part by grants from NIH NINDS to M.D. and by grants from HFSPO and IMBB to N.T.

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Author notes

  1. Keli Xu

    Present address: Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada

Authors and Affiliations

  1. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, 71110, Crete, Greece

    Popi Syntichaki & Nektarios Tavernarakis

  2. Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, New Jersey, 08855, USA

    Keli Xu & Monica Driscoll

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Correspondence to Nektarios Tavernarakis.

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Syntichaki, P., Xu, K., Driscoll, M. et al. Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419, 939–944 (2002). https://doi.org/10.1038/nature01108

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