Nuclear transport under stress phenocopies transport defects in models of C9Orf72 ALS

Abstract

The nucleus is the hallmark of eukaryotic life and transport to and from the nucleus occurs through the nuclear pore complex (NPC). There is a multitude of data connecting the nuclear transport machinery - i.e. the NPCs and associated nuclear transport factors - to neurodegenerative diseases, but the mechanisms are not well understood. Using Saccharomyces cerevisiae, we systematically studied how the expression of polyPR and polyGA related to C9Orf72 amyotrophic lateral sclerosis impacts the nuclear transport machinery. We measured the abundance and localization of NPC components and transport factors, and assessed the kinetics of import and export by four transport receptors. PolyPR and polyGA cause distinct, and transport receptor dependent effects. We compared the specific changes in transport to those obtained when cells were exposed to different stress situations or mutations. This comparison showed similar patterns of transport defects in cells lacking specific NTRs and cells expressing polyPR. In contrast, polyGA expressing cells bear resemblance to stress conditions where energy maintenance is decreased. The similarity of the patterns of transport deficiencies suggests that polyPR has a direct effect on nuclear transport via NTRs, while polyGA impacts the energy state of the cell and subsequently changes transport.