2. Academic Validation
  3. A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1

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

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.
PMID: 41720774 DOI: 10.1038/s41467-026-68916-0
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.

Figures
Products
Inhibitors & Agonists