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Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity

RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is...

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Detalles Bibliográficos
Autores principales: Bogaert, Elke, Boeynaems, Steven, Kato, Masato, Guo, Lin, Caulfield, Thomas R., Steyaert, Jolien, Scheveneels, Wendy, Wilmans, Nathalie, Haeck, Wanda, Hersmus, Nicole, Schymkowitz, Joost, Rousseau, Frederic, Shorter, James, Callaerts, Patrick, Robberecht, Wim, Van Damme, Philip, Van Den Bosch, Ludo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077250/
https://www.ncbi.nlm.nih.gov/pubmed/30021151
http://dx.doi.org/10.1016/j.celrep.2018.06.070
Descripción
Sumario:RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins.