TDP-43 stabilizes transcripts encoding stress granule protein G3BP1: potential relevance to ALS/FTD
Sidibe, H.; Khalfallah, Y.; Xiao, S.; Gomez, N.; Tank, E. M. H.; Di Tomasso, G.; Bareke, E.; Aulas, A.; McKeever, P. M.; Melamed, Z.; Destroismaisons, L.; Deshaies, J.-E.; Zinman, L.; Parker, J. A.; Legault, P.; Tetreault, M.; Barmada, S. J.; Robertson, J.; Vande Velde, C.
Show abstract
TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. G3BP1 (Ras-GAP SH3-domain-binding protein 1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3UTR. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data suggest that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.
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