ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative...

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• UPF1-mediated mRNA decay is vital for cellular homeostasis but its role in neurons and amyotrophic lateral sclerosis (ALS) is unclear.
• ALS is a neurodegenerative disease linked to TDP-43 pathology and impaired mRNA metabolism.

Approach:

• Utilized human induced pluripotent stem cell (iPSC)-derived spinal motor neurons (MNs).
• Integrated RNA sequencing (RNA-seq) before and after UPF1 knockdown with RNA immunoprecipitation sequencing (RIP-seq) targeting phosphorylated UPF1.
• Identified bona fide UPF1 targets in MNs and analyzed TDP-43's role in UPF1 activity.

Key Points:

• Identified specific UPF1 mRNA targets in MNs, enriched for autophagy and long, GC-rich 3' UTRs, but not premature termination codons.
• TDP-43 depletion reduced UPF1 phosphorylation, impairing mRNA surveillance and upregulating UPF1 targets.
• UPF1 and TDP-43 co-regulate alternative polyadenylation and 3' UTR length in synaptic and axonal function genes.

Conclusions:

• Provides a detailed map of UPF1-mediated mRNA decay in neurons.
• Highlights overlapping functions of UPF1 and TDP-43 in regulating 3' UTR length.
• Offers new insights into RNA metabolism dysfunction in ALS pathogenesis.