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

• Published in: Scientific reports Vol. 6; no. 1; p. 20877
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.02.2016; Nature Publishing Group
• Subjects: 631/378/1689/1285; 692/617/375/1917/1285; Active Transport, Cell Nucleus - genetics; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Arginine; Arginine - metabolism; Cell Nucleus - metabolism; Dipeptides - chemistry; Disease Models, Animal; Drosophila melanogaster - genetics; Eye - pathology; Frontotemporal dementia; Frontotemporal Dementia - genetics; Genes, Insect; Genetic Testing; Guanosine triphosphate; HeLa Cells; Humanities and Social Sciences; Humans; Insects; Methylation; multidisciplinary; Neurodegeneration; Nuclear transport; Repetitive Sequences, Amino Acid; RNA Interference; Science; Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep20877

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.