TDP-43 dysfunction compromises UPF1-dependent mRNA metabolism in ALS.

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Up-frameshift protein 1 (UPF1) is crucial for mRNA decay, maintaining cellular homeostasis.
• Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) pathology and disrupted mRNA metabolism in motor neurons (MNs).
• The specific role of UPF1 in ALS pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of UPF1 in MNs, particularly in the context of ALS.
• To identify direct UPF1 targets in iPSC-derived MNs.
• To elucidate the interplay between UPF1, TDP-43, and mRNA metabolism in ALS.

Main Methods:

• RNA sequencing (RNA-seq) following UPF1 knockdown.
• RNA immunoprecipitation sequencing (RIP-seq) of phosphorylated UPF1.
• Analysis of iPSC-derived MNs from healthy individuals and ALS patients.

Main Results:

• UPF1 targets are enriched for autophagy and possess GC-rich, long 3' untranslated regions (3' UTRs).
• UPF1 activity is reduced in TDP-43-depleted and ALS patient MNs.
• TDP-43 depletion impairs UPF1 phosphorylation, and they interact RNA-dependently, co-aggregating in ALS tissue.

Conclusions:

• UPF1 activity is diminished in ALS, linked to TDP-43 dysfunction.
• UPF1 and TDP-43 converge on regulating alternative polyadenylation and 3' UTR length, processes disrupted in ALS.
• This study defines the UPF1 mRNA surveillance network in MNs and links RNA decay to ALS neurodegeneration.