TDP-43 pathology triggers SRRM4-dependent cryptic splicing of G3BP1 in ALS/FTD
Fakim, H.; Ghosh, A.; Amzallag, E.; Danino, Y. M.; Triassi, V.; Brown, A.-L.; Pal, N.; Deshaies, J.-E.; Dubinski, A.; Lacombe, A.; Fauchon, C.; Esfahani, A. M.; Ling, K.; Rigo, F.; Jafar-nejad, P.; NYGC ALS Consortium, ; Francis, N. J.; Trempe, J.-F.; Fratta, P.; Coyne, A. N.; Hornstein, E.; Velde, C. V.
Show abstract
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.
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