TY - JOUR T1 - G<sub>4</sub>C<sub>2</sub> repeat RNA mediates the disassembly of the nuclear pore complex in C9orf72 ALS/FTD JF - bioRxiv DO - 10.1101/2020.02.13.947721 SP - 2020.02.13.947721 AU - Alyssa N Coyne AU - Benjamin L Zaepfel AU - Lindsey Hayes AU - Boris Fitchman AU - Yuval Salzberg AU - Kelly Bowen AU - Hannah Trost AU - Frank Rigo AU - Amnon Harel AU - Clive N Svendsen AU - Dhruv Sareen AU - Jeffrey D Rothstein Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/14/2020.02.13.947721.abstract N2 - Nucleocytoplasmic transport, controlled by the nuclear pore complex, has recently emerged as a pathomechanism underlying neurodegenerative diseases including C9orf72 ALS/FTD. However, little is known about the underlying molecular events and the underlying biology in human neurons. Using super resolution structured illumination microscopy of twenty three nucleoporins in nuclei from C9orf72 iPSC derived neurons and postmortem human tissue we identify a unique subset of eight nucleoporins lost from human neuronal nuclei. POM121, an integral transmembrane nucleoporin, appears to coordinate the composition of the nucleoporins within human neuronal nuclei ultimately impacting nucleocytoplasmic transport, and subsequent cellular toxicity in C9orf72 iPSNs. These data suggest that POM121 is a critical nucleoporin in the maintenance of the nuclear localization of specific nucleoporins in human neurons. Moreover, loss of nuclear POM121, as a result of expanded C9orf72 ALS/FTD repeat RNA, initiates a pathological cascade affecting nucleoporin composition within neuronal nuclei, nuclear pore complex function, and overall downstream neuronal survival. ER -