Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway.

Yen-Chen Lin
Meenakshi Sundaram Kumar
Nandini Ramesh
Eric N Anderson
Aivi T Nguyen
Boram Kim
Simon Cheung
Justin A McDonough
William C Skarnes, The Jackson Laboratory
Rodrigo Lopez-Gonzalez
John E Landers
Nicolas L Fawzi
Ian R A Mackenzie
Edward B Lee
Jeffrey A Nickerson
David Grunwald
Udai B Pandey
Daryl A Bosco


Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of amyotrophic lateral sclerosis-fused in sarcoma (ALS-FUS). Expression of ALS-FUS led to a reduction in NCT and nucleoporin (Nup) density within the nuclear membrane of human neurons. FUS and Nups were found to interact independently of RNA in cells and to alter the phase-separation properties of each other in vitro. FUS-Nup interactions were not localized to nuclear pores, but were enriched in the nucleus of control neurons versus the cytoplasm of mutant neurons. Our data indicate that the effect of ALS-linked mutations on the cytoplasmic mislocalization of FUS, rather than on the physiochemical properties of the protein itself, underlie our reported NCT defects. An aberrant interaction between mutant FUS and Nups is underscored by studies in Drosophila, whereby reduced Nup expression rescued multiple toxic FUS-induced phenotypes, including abnormal nuclear membrane morphology in neurons.