Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization

Abstract Gelsolin (gsn), an actin-severing protein, protects neurons from excitotoxic cell death via inactivation of membranous Ca 2+ channels. Its role during apoptotic cell death, however, has remained unclear. Using several models of neuronal cell death, we demonstrate that endogenous gelsolin has anti-apoptotic properties that correlate to its dynamic actions on the cytoskeleton. We show that neurons lacking gelsolin ( gsn −/− ) have enhanced apoptosis following exposure to staurosporine, thapsigargin, or the cholinergic toxin ethylcholine aziridinium (AF64A). AF64A-induced loss of mitochondrial membrane potential and activation of caspase-3 was specifically enhanced in gsn −/− neurons and could be reversed by pharmacological inhibition of mitochondrial permeability transition. Moreover, increased caspase-3 activation and cell death in AF64A-treated gsn −/− neurons were completely reversed by pharmacological depolymerization of actin filaments and further enhanced by their stabilization. In conclusion, actin remodeling by endogenous gelsolin or analogues protects neurons from apoptosis mediated by mitochondria and caspase-3.