Nucleocytoplasmic transport Mechanisms and involvement in neurodegenerative disease

There is a bidirectional communication between the nucleus and the cytoplasm through highly regulated nucleocytoplasmic transport. This process allows the transport of proteins, RNAs, and ribonucleoproteins across the nuclear envelope via the nuclear pore complexes. The nuclear pore complexes are large macromolecular complexes composed of highly conserved proteins called nucleoporins (Nups). Proteins and RNAs are transported across the nuclear pore after binding of cargo transport receptors that interact with specific hydrophobic amino acid repeats of Nups that form a meshwork within the nuclear pore. These transporters include importins that recognize nuclear localization signals (NLS) in their cargo and mediate transport from the cytoplasm to the nucleoplasm and exportins that recognize nuclear export signals (NES) in their cargos and transport their cargo from the nucleus to the cytoplasm. Whereas nucleocytoplasmic transport largely involves protein-protein interactions between transport proteins and nuclear pore Nups, the directionality of transport is determined by a gradient of the small Ras-related nuclear protein (Ran) guanosine triphosphatase (Ran-GTPase). Whereas proteins and most RNA species are transported by these mechanisms, the transport of messenger RNA ribunucleoprotein particles (mRNPs) utilize an independent transport system. Overall, normal nucleocytoplasmic transport mechanisms ensure that transported cargos are retained in their respective compartments and prevent the passage of nonspecific macromolecules. Impaired nucleocytoplasmic transport is a major disease mechanism in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington disease (HD), and tauopathies. Studies in fly and mouse models, in patient-derived induced pluripotent stem cells (iPSCs), and in brain obtained from autopsy have elucidated pathogenic mechanisms that affect nucleocytoplasmic transport in these disorders. The mechanisms of nucleocytoplasmic transport and its involvement on neurodegenerative disorders have been reviewed recently.1-10 © American Academy of Neurology.