PXD069368

PXD069368 is an original dataset announced via ProteomeXchange.

Title	A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1
Description	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.
HostingRepository	iProX
AnnounceDate	2025-10-11
AnnouncementXML	Submission_2025-10-12_19:51:50.129.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mingmyang Yang
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-12 19:47:49	ID requested
⏵ 1	2025-10-12 19:51:50	announced

Dataset with its publication pending

submitter keyword: TDP-43, cryptic splicing, PKN1-5a1, PKN1-N207

Xiaochuan Wang
contact affiliation	Huazhong University of Science and Technology
contact email	Mingmyang23@outook.com
lab head
Mingmyang Yang
contact affiliation	Huazhong University of Science and Technology
contact email	1192697007@qq.com
dataset submitter

iProX dataset URI