TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Nuclear depletion of the RNA-binding protein TDP-43 is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
• TDP-43 loss leads to de-repression of cryptic exons, but cryptic alternative polyadenylation (APA) events have been largely overlooked.
• Cryptic APA events define the 3' end of gene transcripts and can significantly impact protein function.

Conclusions:

• TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events, specifically cryptic APA.
• These findings expand the known consequences of TDP-43 loss, revealing a mechanism that can increase normal protein translation.
• Cryptic APA events represent a significant, previously underappreciated aspect of TDP-43 proteinopathy in neurodegenerative diseases.