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  • Review Article
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Nuclear pore complexes — a doorway to neural injury in neurodegeneration

Nature Reviews Neurology volume 18, pages 348–362 (2022)Cite this article

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Abstract

The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease.

Key points

  • The nuclear pore complex (NPC), which is made up of multiple nucleoporin proteins, mediates nucleocytoplasmic transport, genome organization and gene expression.

  • Accumulating evidence suggests that defects in the NPC and nucleocytoplasmic transport contribute to, or possibly initiate, neurodegenerative diseases such as amyotrophic lateral sclerosis, dementia and Huntington disease.

  • Cell-type-specific NPC composition might underlie differential cellular vulnerability in neurological diseases.

  • Specific nucleoporin mutations can cause a wide range of neurological disorders, including a Huntington disease-like motor neuron disease.

  • Therapeutic strategies with antisense oligonucleotides and small molecules to repair NPC defects or restore altered nucleocytoplasmic transport are in development.

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Fig. 1: Overview of nuclear pore complex structure and subcomplexes.
Fig. 2: Alterations in the nuclear pore complex and nucleocytoplasmic transport in neurodegenerative diseases.
Fig. 3: Pathological progression of changes to the nuclear pore complex and nucleocytoplasmic transport in amyotrophic lateral sclerosis.

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Acknowledgements

A.N.C. is supported by funding from NIH grant K99NS123242. J.D.R. is supported by funding from the ALS Association, ALS Finding a Cure, the Chan Zuckerberg Initiative, the Department of Defense, F Prime, NIH grants P01NS099114, P01NS084974, R01NS094239 and R01NS122236TEDCO, the Muscular Dystrophy Association, The Robert Packard Center for ALS Research Answer ALS Program, and the Virginia Gentleman Foundation.

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  1. Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alyssa N. Coyne & Jeffrey D. Rothstein

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alyssa N. Coyne & Jeffrey D. Rothstein

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A.N.C. and J.D.R. have submitted a patent application (US Patent Application Serial No. 63/111,882) regarding methods for inhibiting CHMP7 expression in neuronal cells for the treatment of neurodegenerative disorders.

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Coyne, A.N., Rothstein, J.D. Nuclear pore complexes — a doorway to neural injury in neurodegeneration. Nat Rev Neurol 18, 348–362 (2022). https://doi.org/10.1038/s41582-022-00653-6

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