Nuclear pore complex during neuronal degeneration: cracking the last barrier!

In eukaryotic cells, the exchange of molecules between the genetic material within the nucleus and the cytosol occurs through the Nuclear Pore Complex (NPC), which is a large membrane-embedded assembly composed by multiple proteins named nucleoporins arranged around an aqueous channel. The bi-directional passive diffusion and the active transport of factors across the nuclear envelope are responsible for a variety of biological processes and they are controlled respectively by the size of the pore and the interaction between nucleoporins and karyopherins. 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. 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.