Measuring and Interpreting Nuclear Transport in Neurodegenerative Disease-The Example of C9orf72 ALS

Transport from and into the nucleus is essential to all eukaryotic life and occurs through the nuclear pore complex (NPC). There are a multitude of data supporting a role for nuclear transport in neurodegenerative diseases, but actual transport assays in disease models have provided diverse outcomes. In this review, we summarize how nuclear transport works, which transport assays are available, and what matters complicate the interpretation of their results. Taking a specific type of ALS caused by mutations in C9orf72 as an example, we illustrate these complications, and discuss how the current data do not firmly answer whether the kinetics of nucleocytoplasmic transport are altered. Answering this open question has far-reaching implications, because a positive answer would imply that widespread mislocalization of proteins occurs, far beyond the reported mislocalization of transport reporters, and specific proteins such as FUS, or TDP43, and thus presents a challenge for future research.

Automated summary

This review discusses the crucial role of nuclear transport in neurodegenerative diseases, the diversity in outcomes of transport assays in disease models, and the challenges in interpreting their results. Using ALS caused by mutations in C9orf72 as an example, it demonstrates the complexity in determining whether the kinetics of nucleocytoplasmic transport are altered. Answering this question has implications for the widespread mislocalization of proteins, beyond the reported mislocalization of transport reporters, and presents a challenge for future research efforts.