Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Dec;15(1):2314297.
doi: 10.1080/19491034.2024.2314297. Epub 2024 Feb 21.

Nuclear pore dysfunction and disease: a complex opportunity

Charlotte M Fare  1 , Jeffrey D Rothstein  1
Affiliations
Review

Nuclear pore dysfunction and disease: a complex opportunity

Charlotte M Fare et al. Nucleus. 2024 Dec.

Abstract

The separation of genetic material from bulk cytoplasm has enabled the evolution of increasingly complex organisms, allowing for the development of sophisticated forms of life. However, this complexity has created new categories of dysfunction, including those related to the movement of material between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions to nuclear integrity and nucleocytoplasmic transport are detrimental to cell survival. This is particularly true in post-mitotic neurons, where nuclear pore injury and errors to nucleocytoplasmic trafficking are strongly associated with neurodegenerative disease. In this review, we summarize the current understanding of nuclear pore biology in physiological and pathological contexts and discuss potential therapeutic approaches for addressing nuclear pore injury and dysfunctional nucleocytoplasmic transport.

Keywords: Neurodegenerative disease; nuclear envelope; nuclear pore complex; nucleocytoplasmic transport; nucleoporin; therapeutics.

PubMed Disclaimer

Conflict of interest statement

JDR has pending patents on 1) increasing/restoring expression of POM121 for mitigation of NPC injury and TDP-43 dysfunction in neurodegeneration, 2) CHMP7 therapy (ASO, protein degradation, siRNA) in ALS, dementia (AD/FTD), neurodegeneration, and other neurological disorders, and 3) other relevant pending patents regarding nuclear biology and neurodegeneration.

Figures

Panel A: A table listing the Nups contained within each subdomain of the Nuclear Pore Complex, including cytoplasmic filaments, the coat nucleoporin complex, the inner ring, the central channel, transmembrane Nups, and the nuclear basket. Panel B: A cartoon diagram of a Nuclear Pore Complex within the nuclear envelope.
Figure 1.
The nuclear pore complex is a large macromolecular structure. (a) The nuclear pore complex (NPC) is comprised of six subdomains: the cytoplasmic filaments, the coat nucleoporin complex, the inner ring, the central channel, the transmembrane nucleoporins, and the nuclear basket. Many phenylalanine-glycine (FG)-Nups (indicated by an asterisk) are found in the central channel. However, FG-Nups are also found at the asymmetric cytoplasmic and nuclear faces of the NPC. (b) The NPC sits within the double membrane of the nucleus, and the NPC core demonstrates two-fold symmetry across the nuclear envelope, with the asymmetric cytoplasmic filaments and nuclear basket Nups projecting into their corresponding cellular compartments.
Panel A: A Gaussian surface representation of the symmetric core of the nuclear pore complex shown from the cytoplasmic face, the nuclear face, and on its side, with the cytoplasmic face pointing up. Each Nup that has a mutation associated with disease is shown in a different color, with white showing Nups that have no known associated mutations. Panel B: A Gaussian surface representation of a single nuclear pore complex monomer shown from four different angles. The coloring scheme in panel B is the same as in panel A.
Figure 2.
Mutations to the nucleoporins of the nuclear pore complex are associated with a diverse set of diseases. (a) From left to right, the symmetrical core of the nuclear pore complex (NPC) shown from its cytoplasmic and nuclear faces, as well as from within the plane of the nuclear envelope. Nucleoporins (Nups) that have not been identified to be mutated in disease are shown in white. Mutated Nups are shown in different colors, labeled on an NPC monomer in (b). Among cytoplasmic Nups, Gle1 is shown in lime, Nup88 is mint green, Nup214 is light green, and Nup358 is seafoam green. For outer coat Nups, Nup37 is light pink, Nup85 is dark purple, Nup107 is fuchsia, Nup133 is salmon, and Nup160 is pink. Of the inner ring Nups, Nup93 is navy, Nup155 is sky blue, Nup188 is teal, and Nup205 is dark periwinkle. The central channel Nup, Nup62, is shown in lilac. Additional Nups with disease associated mutants that are not included in these structures are: cytoplasmic Nup, AAAS; basket Nups, Nup50 and TPR. Structures shown are PDB: 7TBL [59].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Webster BM, Lusk CP.. Border safety: quality control at the nuclear envelope. Trends Cell Biol. 2016;26:29–30. doi:10.1016/j.tcb.2015.08.002 - DOI - PMC - PubMed
    1. Robijns J, Houthaeve G, Braeckmans K, et al. Loss of nuclear envelope integrity in aging and disease. Int Rev Cell Mol Biol. 2018;336:205–222. - PubMed
    1. Lindenboim L, Zohar H, Worman HJ, et al. The nuclear envelope: target and mediator of the apoptotic process. Cell Death Discov. 2020;6(1):29. doi: 10.1038/s41420-020-0256-5 - DOI - PMC - PubMed
    1. Gauthier BR, Comaills V. Nuclear envelope integrity in health and disease: consequences on genome instability and inflammation. IJMS. 2021;22(14):7281. doi: 10.3390/ijms22147281 - DOI - PMC - PubMed
    1. Metuzals J, Robitaille Y, Houghton S, et al. Paired helical filaments and the cytoplasmic-nuclear interface in Alzheimer’s disease. J Neurocytol. 1988;17(6):827–833. doi: 10.1007/BF01216709 - DOI - PubMed

MeSH terms

Substances

Grants and funding

This work was supported by: Answer ALS (JDR), NIH NIA R01 RF1AG062171 (JDR), Chan Zuckerberg Foundation (JDR), NIH NINDS 2P01NS084974, R01 NS122236 (JDR) R35 NS132179 (JDR), ALS Association (JDR), Muscular Dystrophy Association (JDR), Virginia Gentlemen Foundation (JDR), US Dept of Defense HT94252310136 (JDR), and F Prime (JDR).