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. 2026 Feb 20.
doi: 10.1038/s41467-026-68916-0. Online ahead of print.

A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1

Mingming Yang #  1   2   3 , Qi Wang #  2   3 , Ruolan Yan #  4   5 , Dongkun Kang  2   3 , Weihan Luo  6 , Liti Zhang  4 , Rong Liu  2   3 , Liyong Wu  7   8 , Jianlan Gu  9   10 , Xiaochuan Wang  11   12   13   14
Affiliations

A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1

Mingming Yang et al. Nat Commun. .

Abstract

Dysfunction of transactive response DNA-binding protein 43 (TDP-43) drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), in part through inducing aberrant RNA splicing. However, whether such mis-splicing yields stable, pathogenic proteins remains unclear. Here, we identify a TDP-43-repressed cryptic exon in Protein kinase N1 (PKN1), designated PKN1-5a1, which is activated in ALS patient brains and introduces a premature termination codon. This aberrant transcript escapes nonsense-mediated decay and is translated into a truncated peptide, PKN1-N207 (PKN207), detectable in AD brains with TDP-43 pathology. In mice, PKN207 impairs cognition, memory, and synaptic plasticity. Our findings demonstrate that TDP-43 loss-induced cryptic splicing can generate stable neurotoxic polypeptides, revealing a peptide-mediated mechanism in TDP-43 proteinopathies.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

    1. Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650–655 (2015).
    1. Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14, 459–468 (2011).
    1. Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14, 452–458 (2011).
    1. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
    1. Long, Z. et al. Amyotrophic lateral sclerosis features predict TDP-43 pathology in frontotemporal lobar degeneration. Neurobiol Aging 107, 11–20 (2021).