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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The RNA-binding protein TDP-43 is known to be depleted from neuronal nuclei in frontotemporal dementia and amyotrophic lateral sclerosis.
• TDP-43's established role involves repressing cryptic exon inclusion during pre-mRNA splicing.
• Its involvement in other RNA processing events remains largely unexplored.

Purpose of the Study:

• To investigate the role of TDP-43 in alternative polyadenylation (APA) in human neurons.
• To determine if TDP-43 dysfunction is linked to APA changes in neurodegenerative diseases.

Main Methods:

• High-resolution polyadenylation site mapping was employed.
• TDP-43-regulated APA events were comprehensively defined in human stem cell-derived neurons.
• The influence of TDP-43 binding strength and position on polyA site usage was analyzed.

Main Results:

• Loss of TDP-43 in neuronal nuclei and disease-associated mutations correlate with widespread APA changes.
• TDP-43 binding characteristics dictate polyA site usage.
• TDP-43-driven APA alterations affect the expression of key disease-related genes, including SFPQ, NEFL, and TMEM106B.

Conclusions:

• Alternative polyadenylation changes represent a novel aspect of TDP-43 pathology, beyond its known role in splicing.
• Dysregulation of APA due to TDP-43 loss contributes to the molecular mechanisms underlying frontotemporal dementia and amyotrophic lateral sclerosis.