Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

• Published in: Nature neuroscience Vol. 18; no. 9; pp. 1226 - 1229
• Main Authors: Jovičić, Ana, Mertens, Jerome, Boeynaems, Steven, Bogaert, Elke, Chai, Noori, Yamada, Shizuka B, Paul, Joseph W, Sun, Shuying, Herdy, Joseph R, Bieri, Gregor, Kramer, Nicholas J, Gage, Fred H, Van Den Bosch, Ludo, Robberecht, Wim, Gitler, Aaron D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2015; Nature Publishing Group
• Subjects: 14/63; 631/378/2583; 692/699/375/365/1917; Active Transport, Cell Nucleus - physiology; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedicine; brief-communication; C9orf72 Protein; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cells, Cultured; Dipeptides - genetics; Dipeptides - metabolism; DNA Repeat Expansion - physiology; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Gene Deletion; Gene mutations; Genes; Genetic aspects; Genomes; Health aspects; Humans; Localization; Medical research; Medicine; Mice; Neurobiology; Neurodegeneration; Neurosciences; Pathogenesis; Proteins; Proteins - genetics; Proteins - metabolism; Risk factors; Saccharomyces cerevisiae; Toxicity; Yeast; Yeasts; United States; La Jolla California; California; Belgium; United States > US
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.4085

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. With unbiased screens in Saccharomyces cerevisiae , Jovicic et al . identified potent modifiers of toxicity of dipeptide repeat proteins produced by unconventional translation of the C9orf72 repeat expansions, pointing to nucleocytoplasmic transport impairments as potential disease mechanisms. 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.