Cited by 262Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesAlzheimer's disease research and treatments

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Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

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Boeynaems, Steven, Bogaert, Elke, Michiels, Emiel, Gijselinck, Ilse, Sieben, Anne, Jovičić, Ana, De Baets, Greet, Scheveneels, Wendy, Steyaert, Jolien, Cuijt, Ivy, Verstrepen, Kevin J., Callaerts, Patrick, Rousseau, Frederic, Schymkowitz, Joost, Cruts, Marc, Van Broeckhoven, Christine, Van Damme, Philip, Gitler, Aaron D., Robberecht, Wim, Van Den Bosch, Ludo·2016·Scientific Reports

DOI 10.1038/srep20877PMC PMC4751451

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Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

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Figure 1 Genes implicated in nuclear transport are potent modifiers of PR toxicity in Drosophila. (a) Expression of a PR25 construct in the fly eye induces a moderate degenerative eye phenotype compared to the eyes of non-affected PA-expressing flies or severely affected flies expressing two copies of the PR25 transgene. (b) Setup of RNAi screen for PR25 modifiers. (c) Knockdown of four karyopherins (Trn, Fs(2)Ket, Kap-alpha3 and Ranbp11) strongly enhanced PR toxicity. (d) Knockdown of RanGTP cycle regulators Rangap and Rcc1 both enhance eye degeneration. (e) Knockdown of some nuclear pore complex components (Nup50, Nup107 and Nup154) suppressed degeneration others (Nup44A, Nup62, Nup93-1) enhanced the phenotype. (a,e) show males, (c,d) females.CC BY · PubMed Central

Figure 2 Transportin-1 and arginine methylation are directly implicated in DPR models and C9 patients. (a) Trn knockdown potently enhanced the PR-induced degenerative eye phenotype. Females are shown. (b) Computational conformational docking predictions predict that PR can fit the transportin-1 binding pocket. Positive arginine side chains of PR (red) interact with the negative side chains (blue) of the binding pocket. (c) Elav is mislocalized to the cytoplasm in PR expressing flies. Mislocalization is exacerbated upon Trn RNAi knockdown. Arrowheads indicate cytoplasmic staining. Scale bar indicates 5 μm. (d) hnRNPA3 is mislocalized in c9FTD cases (arrowheads) but not in disease-negative controls. Picture shows dentate gyrus. Scale bar indicates 10 μm. (e) Art1 knockdown enhances the PR-induced eye phenotype. Males are shown. (f) PR colocalizes with PRMT1 upon cotransfection in HeLa cells, as determined by super resolution microscopy (SIM). (g) GR staining associates with (arrowheads) and partially colocalizes with (arrow) ASYM24 staining in transfected neuroblastoma cells, as determined by SIM. Scale bars indicate 10 μm. (h) Immunostaining with ASYM24 detects methylated pathological aggregates (arrowheads) in dentate gyrus of c9FTD patient samples but not in controls. Scale bar indicates 10 μm.CC BY · PubMed Central

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Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192–1194 (2014). · DOI · Paper page

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Authors: Boeynaems, S., Bogaert, E., Michiels, E., Gijselinck, I., Sieben, A., Jovičić, A., De Baets, G., Scheveneels, W., Steyaert, J., Cuijt, I., Verstrepen, K. J., Callaerts, P., Rousseau, F., Schymkowitz, J., Cruts, M., Van Broeckhoven, C., Van Damme, P., Gitler, A. D., Robberecht, W., & Van Den Bosch, L.
Affiliations: VIB-KU Leuven Center for Brain & Disease Research (BE)
University of Antwerp (BE)
Stanford Medicine (US)
KU Leuven (BE)
ORCID: Boeynaems, Steven
Michiels, Emiel
Sieben, Anne
Jovičić, Ana
Steyaert, Jolien
Cuijt, Ivy
Verstrepen, Kevin J.
Callaerts, Patrick
Schymkowitz, Joost
Cruts, Marc
Gitler, Aaron D.
Venue: Scientific Reports
Publisher: Springer Science and Business Media LLC
Published: 2016-02-12
Volume: 6
Issue: 1
Pages: 20877-20877
ISSN: 2045-2322 (ISSN-L)
DOI: 10.1038/srep20877
PMC: PMC4751451
OpenAlex: W2309375248
Semantic Scholar: dc423dfe17daef5834c89e5fc34a3236305be9c9
Cited by: 262
References: 30
Citations by year: 2026: 6 · 2025: 6 · 2024: 14 · 2023: 25 · 2022: 15 · 2021: 47 · 2020: 37 · 2019: 29 · 2018: 40 · 2017: 27 · 2016: 16
FWCI: 28.08
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Scientific Reports (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Lirias (submittedVersion, cc-by)
Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
Funders: Association Belge contre les Maladies Neuro-Musculaires
Johns Hopkins University
Target ALS
Belgian Federal Science Policy Office (P7/16)
Fonds Wetenschappelijk Onderzoek (G098314N)
KU Leuven
Onderzoeksraad, KU Leuven
Universiteit Antwerpen (FP7/2007-2013)
Vlaamse regering
Fondation pour la Recherche sur Alzheimer
National Institutes of Health (FP7/2007-2013)
National Institute of Neurological Disorders and Stroke (R01NS073660, R01NS065317)
FP7 Ideas: European Research Council (241426, 340429)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: C9orf72, hexanucleotide repeat expansion, dipeptide repeat proteins, nuclear transport, importins, exportins, nuclear pore complex, modifier screen, Drosophila model, amyotrophic lateral sclerosis, frontotemporal lobar degeneration
MeSH terms: Amyotrophic Lateral Sclerosis, Animals, Arginine, Cell Nucleus, Dipeptides, Disease Models, Animal, Drosophila melanogaster, Eye, Genetic Testing, HeLa Cells, Humans, Methylation, Genes, Insect, Repetitive Sequences, Amino Acid, Active Transport, Cell Nucleus, RNA Interference, Frontotemporal Dementia

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Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

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