Mislocalization of Nup62 Contributes to TDP-43 Proteinopathy in ALS/FTLD

Abstract

The nucleocytoplasmic transport (NCT) is impaired in C9-ALS/FTLD, a common genetically caused form of ALS and FTLD. The NCT is regulated by proteins called FG-nucleoporins (FG-Nups), with domains enriched in phenylalanine-glycine repeats. However, the relationship between FG-Nups and TDP-43, an RBP found to be mislocalized in ALS/FTLD patients, has not been defined. A recent study found that a critical protein, FG-Nup62, is mislocalized both in vivo and in vitro in diseased states. The mislocalized Nup62 was colocalized with TDP-43 in cytoplasmic inclusions and promoted its liquid-to-solid transition. The work highlights the involvement of Nup62 in the pathogenesis of ALS/FTLD and the interaction between Nup62 and TDP-43.

Keywords: ALS/FTLD; FG-Nups; Nucleocytoplasmic transport; Nup62; TDP-43; TDP-43 condensates; amyotrophic lateral sclerosis; proteinopathy.