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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 (TAR DNA-binding protein 43) dysfunction is linked to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• Loss of TDP-43 function causes cryptic exon inclusion in RNA transcripts, potentially leading to cellular dysfunction via loss-of-function mechanisms.

Approach:

• Utilized coordinated transcriptomic and proteomic analyses in TDP-43 depleted induced pluripotent stem cell (iPSC)-derived neurons.
• Identified peptides mapping to cryptic exons, validating findings in patient-derived brain tissue and cerebrospinal fluid (CSF).

Key Points:

• Demonstrated de novo protein synthesis from cryptic exon-containing transcripts in TDP-43 deficient models and disease.
• Cryptic exons found in iPSC models accurately predicted those in TDP-43 proteinopathy brains, including those generating novel proteins.
• Inclusion of cryptic peptide sequences altered protein interactions and cellular functions.

Conclusions:

• Cryptic exon translation represents a novel mechanism in TDP-43 proteinopathy pathophysiology.
• The presence of de novo cryptic peptides in ALS patient CSF suggests potential for new biomarker development.