TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are linked to the depletion of the nuclear RNA-binding protein TDP-43.
• TDP-43 loss is known to cause cryptic exon inclusion, but its broader impact on RNA processing remains unclear.

Purpose of the Study:

• To investigate the role of TDP-43 in alternative polyadenylation (APA).
• To determine if TDP-43 loss affects the expression of disease-relevant genes through APA.

Main Methods:

• Analysis of RNA processing events in the context of TDP-43 depletion.
• Gene expression profiling to identify affected genes.

Main Results:

• TDP-43 loss results in significant, widespread alterations in alternative polyadenylation patterns.
• Expression of critical disease-associated genes, including ELP1, NEFL, and TMEM106B, is impacted by these APA changes.
• Evidence suggests APA is a novel component of TDP-43 pathology.

Conclusions:

• Alternative polyadenylation is a significant RNA processing event dysregulated by TDP-43 loss.
• Altered APA contributes to the molecular pathology of FTD and ALS by affecting disease-relevant gene expression.