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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Transactive response DNA-binding protein 43 (TDP-43) dysfunction is implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD).
• TDP-43's role in aberrant RNA splicing is known, but whether this leads to stable, pathogenic proteins is unclear.

Purpose of the Study:

• To investigate if TDP-43 loss-induced aberrant splicing generates stable, pathogenic proteins.
• To identify specific cryptic exons and their resulting peptides in TDP-43 proteinopathies.

Main Methods:

• Identification of TDP-43-repressed cryptic exons using patient brain samples (ALS, AD).
• Analysis of RNA splicing patterns and transcript stability (nonsense-mediated decay).
• Protein expression analysis and functional studies in mouse models.

Main Results:

• A TDP-43-repressed cryptic exon (PKN1-5a1) in Protein kinase N1 (PKN1) was identified and found activated in ALS brains.
• This aberrant transcript leads to a premature termination codon and produces a stable, truncated peptide, PKN1-N207 (PKN207).
• PKN207 was detected in AD brains with TDP-43 pathology and impaired cognition, memory, and synaptic plasticity in mice.

Conclusions:

• TDP-43 loss-induced cryptic splicing can produce stable, neurotoxic polypeptides.
• A peptide-mediated mechanism contributes to the pathogenesis of TDP-43 proteinopathies.
• PKN1-N207 represents a novel pathogenic factor in neurodegeneration.