Nuclear pore dysfunction and disease: a complex opportunity

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 pore complex
• nucleocytoplasmic transport
• nucleoporin
• nuclear envelope
• therapeutics

Acknowledgments

We thank Muzi (Andrew) Du and S. Can Akerman for their feedback on this review.

Disclosure 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.

Author contributions

CMF and JDR prepared the manuscript concept, outline, and draft. All authors reviewed and edited the manuscript.

Additional information

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).