Dataset Information

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

ABSTRACT: Transactive response DNA-binding protein 43 (TDP-43) is a key factor in maintaining the fidelity of neuronal RNA splicing, and its dysfunction is observed in amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) with TDP-43 pathology. Although loss of TDP-43 can activate multiple cryptic splicing events, whether specific cryptic exons generate stable and toxic peptides remains unclear. Here, we identify a TDP-43–dependent cryptic splicing event (PKN1-5a1) in the serine/threonine kinase gene PKN1: in transcriptomes of ALS patient brains it is markedly activated, inserting a 127-bp unannotated exon and introducing multiple premature termination codons. We further show that this aberrant transcript can partially escape nonsense-mediated mRNA decay (NMD) and is translated into a truncated peptide, N207; in AD brains with TDP-43 pathology, N207 is also detected by a specific antibody. Functional studies indicate that N207 overexpression impairs cognitive behaviors and weakens synaptic plasticity. These results indicate that cryptic splicing resulting from dysregulated TDP-43 not only causes loss of protein function but can also generate truncated toxic peptides that evade NMD, providing a new molecular-level explanation for the pathogenesis of TDP-43–related proteinopathies.

ORGANISM(S): Mus Musculus

SUBMITTER: Xiaochuan Wang

PROVIDER: PXD069368 | iProX | Sat Oct 11 00:00:00 BST 2025

REPOSITORIES: iProX

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

Yang Mingming M Wang Qi Q Yan Ruolan R Kang Dongkun D Luo Weihan W Zhang Liti L Liu Rong R Wu Liyong L Gu Jianlan J Wang Xiaochuan X

Nature communications 20260220 1

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 tr ...[more]

PMID: 41720774

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Dataset Information

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

Publications

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

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