Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.298455v1?rss=1 Authors: 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. 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 3'UTR. 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. Copy rights belong to original authors. Visit the link for more info