Neuronal regeneration: a role for apoptotic proteins

The ability to stimulate functional neuronal regeneration would markedly enhance treatment of brain injuries and neurodegenerative diseases. In studies of C. elegans, Pinan-Lucarre et al. uncovered unexpected roles for apoptotic proteins in promoting neuronal regeneration that might be conserved across species. Worms mutant for CED-3, the core executioner apoptotic protease in C. elegans, had slower axonal outgrowth and delayed neuronal reconnections after laser-mediated injury. The CED-3-activating protein CED-4 [homologue of mammalian apoptosis protease activating factor-1 (Apaf-1)], but not other upstream apoptotic proteins, was also important. They also linked CED-3 and CED-4 to a pathway involving DLK-1, a kinase implicated in regeneration across species. Finally, they showed that this regenerative pathway involves Ca²⁺ signalling (known to be important in neuronal responses to injury) and specifically the conserved Ca²⁺-binding protein calreticulin. The authors propose a model whereby injury-induced Ca²⁺ signalling amplified by calreticulin promotes CED-4-mediated activation of CED-3, which then acts upstream of a DLK-1-mediated regenerative pathway. These data uncover a previously unknown pathway that will guide future studies of neuronal regeneration in higher organisms.