Counter-regulation of RNA stability by UPF1 and TDP43

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Nonsense-mediated mRNA decay (NMD) is a critical RNA quality control pathway that degrades transcripts with premature termination codons (PTCs).
• Dysregulation of NMD is implicated in human diseases, making accurate quantification of NMD status essential for disease research and biomarker discovery.
• NMD plays a role in regulating gene expression and maintaining RNA homeostasis.

Approach:

• Developed and validated a next-generation sequencing approach (NMDq) to identify and quantify PTC-containing transcripts.
• Applied NMDq to assess NMD pathway activity in models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Investigated the role of the master NMD regulator UPF1 in regulating RNA homeostasis and NMD activity.

Key Points:

• NMDq successfully validated for tracking RNA surveillance and measuring PTC-containing transcripts.
• No significant differences in PTC-encoding transcripts were detected in ALS models or disease, challenging the role of canonical NMD in ALS/FTD pathogenesis.
• UPF1 overexpression did not significantly alter PTC transcript clearance but restored RNA homeostasis via regulation of alternatively poly-adenylated isoforms.

Conclusions:

• Canonical NMD is not a significant contributor to the pathogenesis of ALS and FTD.
• UPF1 promotes neuronal survival by regulating transcripts with extended 3' untranslated regions, independent of direct PTC clearance.
• The findings suggest alternative mechanisms beyond canonical NMD are involved in ALS/FTD RNA dysregulation.