mRNA mislocalization following TDP-43 loss

mRNAs localization to neuronal projections help brain respond to external cues but mechanisms that govern their localization are unknown.

The researchers show in this study that loss of TDP-43  results in significant accumulation dozens of mRNAs in the neurites.

They also demonstrate that these mRNAs are highly enriched for TDP-43 binding sites in their 3′-UTRs. Specific motifs within these UTRs are necessary and sufficient for TDP-43-dependent mRNA localization and directly bind recombinant TDP-43 in vitro. The same motifs also regulate mRNA stability in a TDP-43-dependent manner.

The researchers show that the expression of ALS-associated TDP-43 mutants results  in mRNA mislocalization as seen during loss of TDP-43.

https://link.springer.com/article/10.1038/s44318-025-00653-4

https://sciencemission.com/TDP-43-directly-inhibits-mRNA-accumulation