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Letters to Nature
Nature 419, 939-944 (31 October 2002) | doi:10.1038/nature01108; Received 3 July 2002; Accepted 21 August 2002
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Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans
Popi Syntichaki1, Keli Xu2,3, Monica Driscoll2 & Nektarios Tavernarakis1
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion 71110, Crete, Greece
- Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08855, USA
- Present address: Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto Ontario, M5G 1X8, Canada.
Correspondence to: Nektarios Tavernarakis1 Correspondence and requests for materials should be addressed to N.T. (e-mail: Email: tavernarakis@imbb.forth.gr).
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
-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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