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

Sidibé, Hadjara; Khalfallah, Yousra; Xiao, Shangxi; Gómez, Nicolás; Tank, Elizabeth M.H.; Tomasso, Geneviève Di; Bareke, Eric; Aulas, Anaïs; McKeever, Paul M.; Melamed, Ze’ev; Destroismaisons, Laurie; Deshaies, Jade-Emmanuelle; Zinman, Lorne; Parker, Jennifer; Legault, Pascale; Tétreault, Martine; Barmada, Sami J.; Robertson, Janice; Velde, Christine Vande

doi:10.1101/2020.09.15.298455

Cited by 3 publications

(7 citation statements)

References 74 publications

(112 reference statements)

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“…regions, with the longer transcript being the predominant one expressed in the cerebellum compared to the frontal cortex (Sidibé et al, 2020). This implies that the relevance of this regulatory mechanism may vary within the CNS.…”

Section: Regulation Of G3b P1 Mrnamentioning

confidence: 99%

“…Indeed, TDP-43 depletion results in decreased G3BP1 protein levels (McDonald et al, 2011) and recent work has uncovered that this is because of TDP-43 binding and stabilizing the short G3BP1 transcript via a conserved 16-nt element located within the 3'UTR (Sidibé et al, 2020). This work also demonstrated that G3BP1 mRNA levels are compromised in ALS/ FTD neurons featuring TDP-43 inclusions with concomitant nuclear depletion (Sidibé et al, 2020). Whether this is also true in other diseases featuring TDP-43 pathology remains to be demonstrated.…”

Section: Regulation Of G3b P1 Mrnamentioning

confidence: 99%

“…The authors suggest that the loss of endogenous TDP-43 is not responsible for the toxicity associated with TDP-43 over-expression and that cell death resulting from the absence or overabundance of TDP-43 is via distinct mechanisms (Barmada et al, 2015). Given that TDP-43 regulates G3BP1 (Sidibé et al, 2020), it is plausible that in the context of TDP-43 nuclear depletion, the lack of G3BP1 impedes UPF1 from carrying out its SRD-related functions, resulting in toxicity. Moreover, FUS mutant proteins disturb stress granule disassembly such that G3BP1 remains in the granules longer than intended (Baron et al, 2013).…”

Section: G3bp1 and Structure-mediated Rna Decaymentioning

confidence: 99%

“…Notably, the DDX5‐binding site is only present on the short G3BP1 transcript (Figure 1). Recent evidence indicates that G3BP1 transcripts are differentially expressed in different CNS regions, with the longer transcript being the predominant one expressed in the cerebellum compared to the frontal cortex (Sidibé et al, 2020). This implies that the relevance of this regulatory mechanism may vary within the CNS.…”

Section: Regulation Of G3bp1 Mrnamentioning

confidence: 99%

“…It is notable that cytoplasmic inclusions of TDP‐43 are almost always associated with TDP‐43 nuclear depletion, suggesting TDP‐43 loss‐of‐function mechanisms may underlie these diseases. Indeed, TDP‐43 depletion results in decreased G3BP1 protein levels (McDonald et al, 2011) and recent work has uncovered that this is because of TDP‐43 binding and stabilizing the short G3BP1 transcript via a conserved 16‐nt element located within the 3’UTR (Sidibé et al, 2020). This work also demonstrated that G3BP1 mRNA levels are compromised in ALS/FTD neurons featuring TDP‐43 inclusions with concomitant nuclear depletion (Sidibé et al, 2020).…”

Section: Regulation Of G3bp1 Mrnamentioning

confidence: 99%

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The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

Sidibé

Dubinski

Velde

2021

Journal of Neurochemistry

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Since its discovery in 1996 as a RAS-binding partner, Ras-GTPaseactivating protein (GAP)-binding protein 1 (G3BP1) has been linked to a variety of biological processes, molecular functions and cellular compartments (Parker et al., 1996). Initially suggested to play a key role in the Ras signaling pathway via direct binding to Ras, more recent evidence contradicts this potential function (Annibaldi et al., 2011;Xu et al., 2013). Even if this initial function is debated, based on its role in development, RNA metabolism, degradation and stress response, G3BP1 seems to be a jack-of-all-trades protein that is fundamental to cellular homeostasis.

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Section: Regulation Of G3b P1 Mrnamentioning

confidence: 99%

Section: Regulation Of G3b P1 Mrnamentioning

confidence: 99%

Section: G3bp1 and Structure-mediated Rna Decaymentioning

confidence: 99%

Section: Regulation Of G3bp1 Mrnamentioning

confidence: 99%

Section: Regulation Of G3bp1 Mrnamentioning

confidence: 99%

See 3 more Smart Citations

The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

Sidibé

Dubinski

Velde

2021

Journal of Neurochemistry

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The Batten disease protein CLN3 is important for stress granules dynamics and translational activity

Relton

Roth

Yasa

et al. 2022

Preprint

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The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganising cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions and signalling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent of aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis (JNCL), a rare neurodegenerative disease affecting children. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa KO model, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signalling. We further demonstrate that loss of CLN3 results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.

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A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Marrero-Gagliardi,

Noda,

Zanovello

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive degeneration of motor neurons in the cerebral cortex and spinal cord, with a rapid progression from diagnosis to death. The great majority of ALS cases and around 50% of FTD cases present with TDP-43 pathology, leading to mislocalization and cytoplasmic aggregation of TDP-43, which can result in both its loss of nuclear functions and a gain of toxicity in the cytoplasm. TDP-43 and other RNA-binding proteins accumulate in stress granules (SGs) under stress conditions. The ubiquitin-specific protease 10 (USP10) is an inhibitor of SGs assembly that has been recently linked to neurodegeneration. Here, we identified a new functional interaction between TDP-43 and USP10, in which USP10 can control multiple aspects of TDP-43 biology that are thought to play important roles in its involvement in disease pathogenesis, such as its cytoplasmic and nuclear aggregation, expression and splicing functionality. In turn, TDP-43 is also able to control diverse aspects of USP10 biology, such as its expression levels, aggregation and function. Critically, we found USP10 dysregulation in ALS and FTD patients, overall suggesting a possible role for USP10 in ALS/FTD pathogenesis.

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

Cited by 3 publications

References 74 publications

The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

The Batten disease protein CLN3 is important for stress granules dynamics and translational activity

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

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