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Cited by 125Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingGenetic Neurodegenerative Diseases

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

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Barmada, Sami J., Ju, Shulin, Arjun, Arpana, Batarse, Anthony, Archbold, Hilary C., Peisach, Daniel, Li, Xingli, Zhang, Yuxi +6 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1509744112PMC PMC4485101
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Abstract

Significance: Amyotrophic lateral sclerosis (ALS) is a devastating disorder inevitably resulting in paralysis and death. Mutations in genes encoding RNA binding proteins cause familial ALS, but wild-type (WT) versions of these proteins accumulate in sporadic disease. In this study, we identified and characterized human up-frameshift protein 1 (hUPF1) as a potent modifier of neurodegeneration in ALS models. hUPF1 dramatically reduced toxicity in primary mammalian neurons expressing WT and disease-associated mutant RNA binding proteins, demonstrating efficacy in familial and sporadic disease models, and verifying the existence of a conserved neurotoxic pathway targeted by hUPF1. The work has fundamental implications for ALS disease mechanisms and offers a novel perspective on effective therapies generalizable to both sporadic and familial disease.

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  • Disruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture have likewise been described in ALS/FTLD-TDP samples and disease models.

    “Disruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture — all of which we observed upon NLK overexpression — have likewise been described in ALS/FTLD-TDP samples and disease models (9–11, 50).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [50]

    The Introduction and Discussion describe TDP43 mislocalization and hUPF1-mediated protection in ALS models, but do not address the Ran gradient, nuclear pore components, or pore architecture. Searches for those terms and nuclear transport found no passage in our copy supporting the attributed claim; page numbers were not available. (LLM, conf=0.75)

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Research works printed but not linked: 42

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Authors
Barmada, S. J., Ju, S., Arjun, A., Batarse, A., Archbold, H. C., Peisach, D., Li, X., Zhang, Y., Tank, E. M. H., Qiu, H., Huang, E. J., Ringe, D., Petsko, G. A., & Finkbeiner, S.
Affiliations
  • University of Michigan (US)
  • Wright State University (US)
  • Gladstone Institutes (US)
  • University of San Francisco (US)
  • Brandeis University (US)
  • Weill Cornell Medicine (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-06-08
Volume
112
Issue
25
Pages
7821-7826
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1509744112
PMC
PMC4485101
OpenAlex
W1555539221
Cited by
125
References
3
Citations by year
2026: 8 · 2025: 12 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 15 · 2020: 16 · 2019: 15 · 2018: 14 · 2017: 10 · 2016: 7
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 183 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (1K08NS072233-01A1, 3R01 NS039074, 2R01 NS045091, NS083390)
  • HHS | National Institutes of Health (C06 RR018928)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
amyotrophic lateral sclerosis, frontotemporal dementia, nonsense-mediated mRNA decay, TDP-43, FUS, RNA helicase, neuronal survival, RNA metabolism, RNA-binding proteins
MeSH terms
Amyotrophic Lateral Sclerosis, Cell Survival, Humans, Models, Biological, Neurons, Trans-Activators, Neuroprotective Agents, RNA Helicases, Nonsense Mediated mRNA Decay

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