The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress
Open accessAbstract
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the "c9RAN proteins" thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
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1 retracted
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Self-citationA Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
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The unfolded protein response: controlling cell fate decisions under ER stress and beyond
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Roles of CHOP/GADD153 in endoplasmic reticulum stress
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Impairment of the Ubiquitin-Proteasome System by Protein Aggregation
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GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport
Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., et al. (2015) · Nature · doi:10.1038/nature14974 · Cited by 841
Self-citationC9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
Jovičić, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., Paul, J. W., Sun, S., Herdy, J. R., Bieri, G., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4085 · Cited by 598
Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis
Paganoni, S., Macklin, E. A., Hendrix, S., Berry, J. D., Elliott, M. A., Maiser, S., Karam, C., Caress, J. B., Owegi, M. A., Quick, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1916945 · Cited by 536
Jiang, J., Zhu, Q., Gendron, T. F., Saberi, S., McAlonis-Downes, M., Seelman, A., Stauffer, J. E., Jafar-nejad, P., Drenner, K., Schulte, D., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.006 · Cited by 536
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Metadata
- Authors
- Zhang, Y.-J., Jansen-West, K., Xu, Y.-F., Gendron, T. F., Bieniek, K. F., Lin, W.-L., Sasaguri, H., Caulfield, T., Hubbard, J., Daughrity, L., Chew, J., Belzil, V. V., Prudencio, M., Stankowski, J. N., Castanedes-Casey, M., Whitelaw, E., Ash, P. E. A., DeTure, M., Rademakers, R., Boylan, K. B., Dickson, D. W., & Petrucelli, L.
- Venue
- Acta Neuropathologica
- Published
- 2014-08-31
- Volume
- 128
- Issue
- 4
- Pages
- 505-524
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2038735530
- Cited by
- 337
- References
- 78
- FWCI
- 22.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Zhang, Y.-J., Jansen-West, K., Xu, Y.-F., Gendron, T. F., Bieniek, K. F., Lin, W.-L., Sasaguri, H., Caulfield, T., Hubbard, J., Daughrity, L., Chew, J., Belzil, V. V., Prudencio, M., Stankowski, J. N., Castanedes-Casey, M., Whitelaw, E., Ash, P. E. A., DeTure, M., Rademakers, R., . . . Petrucelli, L. (2014). Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathologica. https://doi.org/10.1007/s00401-014-1336-5
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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