Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction

2026-08-04

Genri Toyama

Shingo Koide

Takuma Yamagishi

Aya Washida

Ryutaro Hanyu

Osamu Onodera

Akihiro Sugai *

DOI：10.1016/j.nbd.2026.107560

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• NES-tagged TDP-43 with intact native terminal exon/3′ UTR autoregulation. • The model showed a cytoplasmic shift, detergent insolubility and nuclear depletion. • Endogenous TDP-43 depletion increased insoluble and fragmented exogenous TDP-43. • Nuclear depletion of TDP-43 weakened autorepression and elevated TARDBP transcripts. • Compensatory TARDBP upregulation failed to restore nuclear function under the bias.

Keywords:

ALS/FTLD

3′ UTR-mediated autoregulation

Nuclear export signal (NES)

Detergent-insoluble TDP-43

TDP-43-dependent splicing

Persistent export bias of TDP-43 under native autoregulation links insoluble accumulation to nuclear dysfunction

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