Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization

Emile S. Pinarbasi, Tolga Caǧatay, Ho Yee Joyce Fung, Ying C. Li, Yuh Min Chook, Philip J. Thomas

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied "ΔNES" mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.

Original languageEnglish (US)
Article number7083
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this