Biology subjects

Deshaies, J.-E.

Publications and source records attributed to Deshaies, J.-E..

2 recordsLinked to original sources

bioRxiv2025

TDP-43 pathology triggers SRRM4-dependent cryptic splicing of G3BP1 in ALS/FTD

Loss of nuclear TDP-43 is a defining feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet how this leads to selective neuronal vulnerability is poorly understood. Here, using human iPSC-derived neurons and a large multi-omics dataset of ALS/FTD patients, we demonstrate that TDP-43 pathology induces the inclusion of an in-frame cryptic exon in human G3BP1. The resulting CRYPTIC G3BP1 protein contains an additional 10-amino acids within the highly conserved NTF2L domain, which acts as a dominant negative and disrupts stress granule dynamics. We further show that cryptic exon inclusion in G3BP1 upon TDP-43 loss is enriched in neurons. Mechanistically, the loss of TDP-43 unmasks a binding site for the neuron-specific splicing regulator SRRM4 within intron 2 of G3BP1, enabling the inclusion of the cryptic exon. Collectively, our findings reveal that neuron-specific regulatory mechanisms intersect with TDP-43 -mediated splicing and suggest a mechanistic basis for the increased neuronal vulnerability observed in ALS/FTD.

neuroscience↗

bioRxiv2020

TDP-43 stabilizes transcripts encoding stress granule protein G3BP1: potential relevance to ALS/FTD

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.

neuroscience↗