Thus, it is not surprising that most of the degenerative programs induce cellular stress by altering the NPC composition or the binding between nucleoporins and docking factors. between nucleoporins and docking factors. This facilitates the access of nuclear DNA to pro-death factors, amplify the detrimental cascade and finally play a role in the disassembly of the nuclear structure. Recently, we have shown that during calcium-mediated neuronal degeneration NPC components can be degraded with consequent increase of NPC channel permeability. Moreover, we proved that these changes occurred much earlier than the final disassembly of the nuclear envelope and they are mediated by calcium overload. Is the increase of NPC leakiness the executioner of the excitotoxic process or simply a final event of a cell condemned to death? Here we speculate the consequence of the nucleoporin loss, the alteration of nucleocytoplasmic transport and their contribution to neuronal demise. Key words:calcium, calpains,C. elegans, excitotoxicity, nucleoporins, nucleus == Introduction KIAA1235 == In eukaryotic cells, the exchange of information between the genetic material within the Pomalidomide-C2-NH2 hydrochloride nucleus and the cytoplasm is required for the coordination of cellular processes.1The movement of macromolecules across the nuclear envelope occurs through the aqueous channel of the NPC, which is composed by multiple copies of about 30 different proteins named nucleoporins responsible for the rigid core scaffold and the selective barrier of the pore.2Essentially, the NPC is composed by five distinct assemblies of nucleoporins on the basis to their locations: the membrane, the outer, the inner and the linker rings and the phenylalanine-glycine (FG) nucleoporins. The first three substructures form the NPC core and anchor the structure to the nuclear envelope, whereas unfolded and clustered regions of FG nucleoporins fill the central channel of the NPC, restrict the passage of molecules through the pore and allow highly selective association with nuclear transport receptors and their cargos.3,4The free diffusion is restricted to molecules smaller than 4050 kDa, whereas the transit of large cargo-complexes through the NPC re-sealing structure is energy dependent and actively regulated.5Moreover, dynamic changes of NPC global structure, including the complete disassembly of the complex, and alteration of nucleoporin composition can occur as essential requirements for the coordination of cellular functions during the different stage of the cell cycle.6,7Clearly, any alteration affecting nuclear transport or the organization of NPC would alter the permeability of the nuclear envelope, with a significant impact on DNA transcriptional regulation and therefore on a range of cellular processes, such as in the case of viral infection. Indeed, several studies have shown that a variety of trafficking pathways are perturbed in virus-infected cells, with an increase leakiness of the nuclear envelope caused by the degradation of some nucleoporins, which facilitates the shuttling of viral macromolecules and therefore viral replication.8Similarly, during apoptosis structural changes of the nuclear envelope and NPC ultimately trigger the re-distribution of pro-apoptotic factors and the consequent amplification of the death-signal.9,10Several proteins have been described to translocate from the cytoplasm to the nucleus during apoptosis, including caspases,11,12which cleave nuclear proteins such as lamins and nucleoporins, Apaf-1,1315the death receptor adaptor protein TRADD16and the mitochondrial proteins Cytochrome C and Apoptosis Inducing Factor (AIF).17In this context, reduction of nuclear trafficking by wheat germ agglutinin (WGA) or antibodies to importins can prevent Fas-induced apoptosis,18as well as viral replication,19which suggests that access to the nucleus is a prerequisite for the coordination of the death program. Thus, Pomalidomide-C2-NH2 hydrochloride crosstalk between the nucleus and the other intracellular compartments is usually tightly coordinated and implicated in a variety of pathological processes. What is the role of the NPC during neuronal demise? Is the NPC a regulatory player or a simple viewer of the show? In the last decade, a growing number of groups have reported that several proteins accumulate in the nucleus of neurons under a variety of stressing conditions and this contributes to cytotoxicity. Importantly, pharmacological or genetic treatments that suppress the improper translocation Pomalidomide-C2-NH2 hydrochloride of factors into the nucleus, such as in the case of GAPDH20,21or HDAC4,22can promote neuronal survival, which means that improper localization of proteins can influence cell death cascade and therefore determine cell fate. We have recently studied the changes in protein localization during excitotoxicity, a process brought on by excessive glutamate release that induces extensive membrane depolarization and neuronal degeneration. We have shown that elevation of calcium facilitates the re-distribution of small-size proteins across the nuclear envelope. Furthermore, calcium-activated proteases, calpains, increase the permeability of the NPC by altering NPC components with consequent impairment of the nuclear transport machinery.23Although calpains are involved in the disassembly of the nucleus (Fig. 1), the detachment of the heterochromatin from the nuclear envelope and the disassembly of the NPC occur much later than the re-distribution of molecules. Thus, our findings shed light on an.
