A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1 PMID: 41720774

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2026 Feb 20;17(1):2963. doi: 10.1038/s41467-026-68916-0.

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

1. Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
2. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3. Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
4. Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China.
5. Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
6. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
7. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China. [email protected].
8. National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China. [email protected].
9. Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China. [email protected].
10. Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. [email protected].
11. Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China. [email protected].
12. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
13. Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
14. Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. [email protected].
# Contributed equally.

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.