Nuclear Pore Dysfunction in Neurodegeneration

Abstract

The nuclear pore complex (NPC) is a large multimeric structure that is interspersed throughout the membrane of the nucleus and consists of at least 33 protein components. Individual components cooperate within the nuclear pore to facilitate selective passage of materials between the nucleus and cytoplasm while simultaneously performing pore-independent roles throughout the cell. NPC dysfunction is a hallmark of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). NPC components can become mislocalized or altered in expression in neurodegeneration. These alterations in NPC structure are often detrimental to the neuronal function and ultimately lead to neuronal loss. This review highlights the importance of nucleocytoplasmic transport and NPC integrity and how dysfunction of such may contribute to neurodegeneration.

Keywords: ALS; Alzheimer’s disease; Huntington’s disease; Neurodegeneration; Nuclear pore complex; Nucleocytoplasmic transport.

Fig. 1

The nuclear pore complex (NPC) is a massive structure comprised of 33 known protein components organized into five main structural domains–the cytoplasmic filaments (yellow), the inner and outer nuclear rings (green), the transmembrane components (purple), the nuclear core components (blue), and the nuclear basket (red) (A). Several nuclear pore components have been found to be disrupted in cases of ALS (colored in black)–Gle1, GP210, NDC1, Nup107, Nup133, Nup153, Nup50, Nup62, Nup98, POM121, RanBP2, and Tpr (B). Nup98 and Nup62 are disrupted in Alzheimer’s disease (C). Cases of Huntington’s disease show disruption of Nup62, Nup88, and Tpr (D). Miscellaneous juvenile neurodegenerative disorders also display disruption in nuclear pore components including ALADIN, Gle1, Nup214, Nup62, Nup88, and RanBP2, many involving a direct mutation in the gene encoding that NPC component (E)