Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS
Open accessAbstract
C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.
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NLK is a proline-directed serine/threonine kinase.
“Nemo-like kinase (NLK)—a proline-directed serine/threonine kinase—promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import.”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [12]
The passages on nuclear import discuss karyopherins, MTR10 and C9orf72 dipeptide-repeat toxicity, but do not identify NLK or describe its kinase activity (Abstract; page unavailable). Searches for “Nemo-like kinase NLK proline-directed serine/threonine kinase” and “NLK TDP43 nuclear import kinase” found no passage addressing the attributed description. (LLM, conf=0.75)
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Cites
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“Genetic screens in ALS model systems have repeatedly uncovered nuclear pore and nucleocytoplasmic transport factors as potent disease modifiers, confirming the significance of these pathways in disease pathogenesis (10–12).”
- Authors
- Jovičić, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., Paul, J. W., Sun, S., Herdy, J. R., Bieri, G., Kramer, N. J., Gage, F. H., Van Den Bosch, L., Robberecht, W., & Gitler, A. D.
- Affiliations
- Stanford Medicine (US)
- Vlaams Instituut voor Biotechnologie (BE)
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Gitler, Aaron D
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-08-26
- Volume
- 18
- Issue
- 9
- Pages
- 1226-1229
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4552077
- OpenAlex
- W1137678651
- Cited by
- 598
- References
- 4
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 31 · 2023: 45 · 2022: 34 · 2021: 71 · 2020: 61 · 2019: 60 · 2018: 81 · 2017: 75 · 2016: 65 · 2015: 19
- FWCI
- 51.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- National Human Genome Research Institute (T32HG000044)
- National Institute of Neurological Disorders and Stroke (R01NS073660, NS069375, K99NS091538, P30NS069375, R00NS091538, NS091538, R01NS065317)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, dipeptide repeat proteins, amyotrophic lateral sclerosis, frontotemporal dementia, nuclear transport, Ran GTPase, karyopherins, repeat expansion, therapeutic target
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Cell Nucleus, Cells, Cultured, Dipeptides, Humans, Proteins, Yeasts, Gene Deletion, Active Transport, Cell Nucleus, DNA Repeat Expansion, Mice, Frontotemporal Dementia
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