TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca2+ signaling in motor neurons

Mutihac, R; Alegre-Abarrategui, Javier; Gordon, David F.; Farrimond, Lucy; Yamasaki-Mann, Michiko; Talbot, Kevin; Wade‐Martins, Richard

doi:10.1016/j.nbd.2014.12.010

Cited by 48 publications

(48 citation statements)

References 44 publications

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“…In motor neurons of ALS‐affected cases, mutant TARDBP is considered to be a determinant of TDP‐43 mislocalization . Our previous and present observations show that, in ALS‐affected patients, mutations of this gene are associated with TDP‐43 cytoplasmic accumulation also in CLM, as well as in lymphocytes and monocytes.…”

Section: Discussionsupporting

confidence: 63%

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Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

Marco

Lomartire

Calvo

et al. 2016

Neuropathology Appl Neurobio

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Section: Discussionsupporting

confidence: 63%

“…The involvement of TDP‐43 in the pathogenesis of ALS has been strengthened by the discovery of several mutations in the TDP‐43 coding gene, TARDBP , in some fALS and sALS cases . These mutations predispose nuclear TDP‐43 to redistribute to the cytoplasm and to form pathological aggregates .…”

Section: Introductionmentioning

confidence: 99%

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

Marco

Lomartire

Calvo

et al. 2016

Neuropathology Appl Neurobio

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“…to non-transfected SH-SY5Y and SH-TDP+, confirming that the A382T mutation is linked to TDP-43 cytoplasmic mislocalisation with formation of inclusions or aggregates (S1 Fig) 7 as previously reported [49,50,51]. Results were the same when using the anti-TDP43 or anti-GFP antibodies.…”

Section: Tdp-43 Nuclear Localization Was Significantly Decreased In Ssupporting

confidence: 86%

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Giannini¹,

Sproviero²,

Bayona-Feliú

et al. 2020

Preprint

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TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

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“…Accumulating evidence suggests the involvement of ER stress in the pathogenic mechanisms of TDP-43 proteinopathies 6, 36. Our results demonstrate that TDP-43 CTFs induces ER stress-mediated apoptosis via increasing expression of phosphorylated eIF2α, CHOP and cleavage of caspase-12.…”

Section: Discussionsupporting

confidence: 52%

“…Previous studies suggested a critical role of ER stress in the pathology of ALS 35, 36. A recent study demonstrated that overexpression of mutant TDP-43 induced ER stress via activation of XBP-1 and ATF6, thus linking ER stress to neurodegeneration 6.…”

Section: Resultsmentioning

confidence: 99%

Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy

Wang¹,

Ma²,

Teng³

et al. 2015

Int. J. Biol. Sci.

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Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.

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TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca2+ signaling in motor neurons

Cited by 48 publications

References 44 publications

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy

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