Alteration of the nuclear pore complex in Ca2 -mediated cell death

作者：Bano D^*; Dinsdale D; Cabrera Socorro A; Maida S; Lambacher N; Mccoll B; Ferrando May E; Hengartner M O; Nicotera P

来源：Cell Death and Differentiation, 2010, 17(1): 119-133.

DOI：10.1038/cdd.2009.112

• calcium
• calpains
• excitotoxicity
• nucleocytoplasmic trafficking
• nucleoporins

Cell death requires coordinated intracellular signalling before disassembly of cell architecture by degradative enzymes. Although the death signalling cascades that involve the mitochondria, the ER and the plasma membrane have been extensively characterized, only a handful of studies have examined the functional and structural alterations of the nuclear pore complex (NPC) during neuronal death. Here, we show that during excitotoxic neuronal degeneration calpains redistributed across the nuclear envelope and mediated the degradation of NPC components causing altered permeability of the nuclear membrane. In primary dissociated neurons, simultaneous recording of cytosolic [Ca2 ] and localization of fluorescent proteins showed that the onset of Ca2 overload signalled a progressive increase in the diffusion of small reporter molecules across the nuclear envelope. Later, calpain-mediated changes in nuclear pore permeability allowed accumulation of large proteins in the nucleus. Further, in a model of excitotoxic neuronal degeneration in Caenorhabditis elegans, we found similar nuclear changes and redistribution of fluorescent probes across the nuclear membrane in dying neurons. Our findings strongly suggest that increased leakiness of the nuclear barrier affects nucleocytoplasmic transport, alters the localization of proteins across the nuclear envelope and it is likely to be involved in Ca2 -dependent cell death, including ischemic neuronal demise. Cell Death and Differentiation (2010) 17, 119-133; doi:10.1038/cdd.2009.112; published online 28 August 2009

• 出版日期2010-1