Cited by 96Nuclear Structure and FunctionAmyotrophic Lateral Sclerosis ResearchHereditary Neurological Disorders

Nuclear pore complexes — a doorway to neural injury in neurodegeneration

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Coyne, Alyssa N., Rothstein, Jeffrey D.·2022·Nature Reviews Neurology

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.

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  • Cell lines 1021 and 793 are control lines, and 883 and 321 are C9ORF lines.

    “The cell lines 1021 and 793 (controls) and 883 and 321 (C9ORF) were generated and characterized as previously described (7).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [7]

    The ‘Nucleocytoplasmic transport alterations’ section discusses C9orf72 iPSC-derived neurons, but does not identify cell lines 1021, 793, 883, or 321. Searches for those identifiers and for the lines’ generation and characterization found no confirming passage in our copy. (LLM, conf=0.75)

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Research works printed but not linked: 3

  1. [35]Melchior F, Paschal B, Evans J & Gerace L Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor. J. Cell Biol 123, 1649– 1659 (1993). 8276887 PMC2290879
  2. [172]US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03626012 (2022). 28792816
  3. [173]US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03945279 (2021). 28792816

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Authors
Coyne, A. N., & Rothstein, J. D.
Affiliations
Johns Hopkins University (US)
Corresponding author
  • Coyne, Alyssa N.
  • Rothstein, Jeffrey D.
Venue
Nature Reviews Neurology
Published
2022-04-29
Volume
18
Issue
6
Pages
348-362
ISSN
  • 1759-4758 (ISSN-L)
  • 1759-4766
OpenAlex
W4225109825
Cited by
96
References
188
Citations by year
2026: 16 · 2025: 24 · 2024: 28 · 2023: 24 · 2022: 4
FWCI
2.08
Type
journal article
Language
en
Open access
Locations
  • Nature Reviews Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Defense
  • Muscular Dystrophy Association
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (P01NS099114, K99NS123242, P01NS084974, R01NS094239, R01NS122236)
  • Robert Packard Center for ALS Research, Johns Hopkins University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
nuclear pore complex, nucleoporins, nuclear transport, neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal dementia, Huntington's disease, nuclear transport receptors, genetic mutations
MeSH terms
Humans, Neurodegenerative Diseases, Active Transport, Cell Nucleus, Nuclear Pore, Nuclear Pore Complex Proteins, Frontotemporal Dementia

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