Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.

Authors

Katie E Copley, Megan M Dykstra, Morgan R Miller, Miriam Linsenmeier, Longsheng Lai, Yuanhang Wang, Yi-Wei Chang, Sami J Barmada, James Shorter

Published in

Science advances. Volume 12. Issue 26. Pages eady0256. Jun 26, 2026. Epub Jun 24, 2026.

Abstract

Prion-like domain (PrLD)-mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.

PMID:
42341118
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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