Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 protein dysfunction is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Loss of TDP-43 function causes cryptic exon inclusion in transcripts, potentially leading to cellular dysfunction.
• The functional consequences of cryptic exon inclusion, particularly protein generation, were not well understood.

Purpose of the Study:

• To investigate whether cryptic exons generated by TDP-43 loss can produce novel proteins.
• To determine if these de novo proteins are detectable in patient samples.
• To explore the functional impact of cryptic exon-derived peptides on protein interactions.

Main Methods:

• Utilized human induced pluripotent stem cell (iPSC)-derived neurons depleted of TDP-43.
• Performed coordinated transcriptomic and proteomic analyses.
• Analyzed cerebrospinal fluid (CSF) from ALS/FTD patients.

Main Results:

• Identified 65 peptides mapping to 12 cryptic exons in TDP-43-depleted neurons.
• Cryptic exons found in neurons predicted those in postmortem brain tissue from TDP-43 proteinopathy patients.
• Detected 18 de novo peptides from 13 genes in CSF of ALS/FTD patients.
• Demonstrated that cryptic peptide sequences altered protein interactions.

Conclusions:

• Cryptic exon translation generates de novo proteins in TDP-43-depleted neurons and ALS/FTD patient CSF.
• This finding reveals novel mechanisms in ALS/FTD pathophysiology.
• De novo peptides in CSF may serve as biomarkers for TDP-43 function.