TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia

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. Ras-GAP SH3-domain-binding protein 1 (G3BP1) 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.

Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels

“…We found >2-fold higher TDP-43 protein levels in Optn 470T BMDMs, also without a change in TARDBP expression ( Figure 2 D–F), demonstrating that our findings in primary microglia were shared by other myeloid cells. TDP-43 has been shown to positively regulate one of the key proteins in stress granule formation- Ras-GAP SH3-domain-binding protein 1 (G3BP1) [ 37 ]. Given that TDP-43 protein levels in Optn 470T primary microglia were increased, we next determined whether this impacted the G3BP1 protein levels.…”

RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

“…To pursue this further, we examined the effect of YTHDF2 knockdown in human neuron disease models. The ALS-associated TDP43(M337V) mutation was introduced into the native TARDBP locus of control human induced pluripotent stem cells (iPSCs) by CRISPR/Cas9 55 . Simultaneously, endogenous TDP43 was labeled at the C-terminus with Dendra2, facilitating identification and selection of clonal cell populations harboring the M337V mutation.…”

“…6C ). iPSCs were then differentiated into forebrain-like neurons (iNeurons) through the induced expression of master transcription factors Ngn1-2, as described previously 40,55,56 . Neurons were tracked by longitudinal microscopy over a 10d period, and their survival assessed by semi-automated tracking software developed specifically for these purposes ( Fig.…”

The Regulatory Role of RNA Metabolism Regulator TDP-43 in Human Cancer

“…That means TDP-43 can regulate stability balance in two aspects: maintain mRNA stability or promote mRNA decay. In the aspect of stability maintenance, a case reported that TDP-43 stabilizes G3BP1 transcripts by targeting a highly conserved cisregulatory element in the 3′ UTR (53). Another report also illustrated that TDP-43 mediated MTORC1-TFEB signaling by partially stabilizing RPTOR/RAPTOR to regulate autophagy (54).…”