Effect of the human SOD1-G93A gene on the Nrf2/ARE signaling pathway in NSC-34 cells

Wang, Fumin; Lu, Yucheng; Qi, Faying; Su, Qiang; Wang, Long; You, Cuiping; Che, Fengyuan; Yu, Jinqing

doi:10.3892/mmr.2014.2087

Cited by 22 publications

(14 citation statements)

References 25 publications

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“…Notably SOD1, the most widely studied protein associated with ALS-FTLD, is also connected with Nrf2 signalling. NSC-34 cells expressing G93A mutant SOD1 displayed an impairment in Nrf2 signalling with decreased numbers of shortened neurites and evidence of increased oxidative stress compared to non-mutant cells ( Wang et al, 2014 ). Likewise in ALS mouse models expressing human SOD1 with the same mutation, activation of the Keap1-Nrf2 pathway did not properly induce the downstream cellular protective proteins in spinal motor neurons ( Mimoto et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

Goode

Rea

Sultana

et al. 2016

Molecular and Cellular Neuroscience

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The transcription factor Nrf2 and its repressor protein Keap1 play key roles in the regulation of antioxidant stress responses and both Keap1-Nrf2 signalling and oxidative stress have been implicated in the pathogenesis of the ALS-FTLD spectrum of neurodegenerative disorders. The Keap1-binding partner and autophagy receptor SQSTM1/p62 has also recently been linked genetically to ALS-FTLD, with some missense mutations identified in patients mapping within or close to its Keap1-interacting region (KIR, residues 347–352). Here we report the effects on protein function of four different disease associated mutations of SQSTM1/p62 which affect the KIR region. Only mutations mapping precisely to the KIR (P348L and G351A) were associated with a loss of Keap1 binding in co-immunoprecipitations comparable to wild-type SQSTM1/p62. These selective effects on Keap1 recognition were entirely rational based on protein structural models. Consistent with impaired Keap1 binding, the P348L and G351A KIR mutants showed reduced ability to activate Nrf2 signalling compared to wild-type SQSTM1/p62 in antioxidant response element (ARE)-luciferase reporter assays. The results suggest that SQSTM1 mutations within the KIR of SQSTM1/p62 contribute to aetiology of some cases of ALS-FTLD through a mechanism involving aberrant expression or regulation of oxidative response genes.

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Section: Discussionmentioning

confidence: 99%

ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

Goode

Rea

Sultana

et al. 2016

Molecular and Cellular Neuroscience

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“…and causes neurite retraction, whereas inhibition of Notch1 signaling promotes neurite extension (Berezovska et al, 1999;Sestan et al, 1999;Bonini et al, 2011). Interestingly, a reduction in neurite length and branching has been observed in mutant SOD1 G93A-induced neuronal injury (Song et al, 2013;Wang et al, 2014). Hes1 negatively controls the expression of proneural genes, including the Neurogenin genes, which are involved in neuritogenesis (Salama-Cohen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

et al. 2015

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“…However, expression of downstream phase II enzymes is reduced (Duan et al, 2010;Wang et al, 2014). In this study, levels of total and cytoplasmic Nrf2 protein were reduced, and nuclear Nrf2 accumulated in NSC-34 cells after transfection with pDEST30-EGFP-TDP-43-M337V.…”

Section: Discussionmentioning

confidence: 52%

“…ALS patients typically die from respiratory muscle paralysis within 3 to 5 years after diagnosis (Mathis et al, 2017). Current evidence suggests that degeneration and death of motor neurons in ALS models are caused by a series of interacting mechanisms including oxidative stress, excitotoxicity, mitochondrial dysfunction, abnormal protein aggregation, cytoskeletal abnormalities, and genetic factors (Wang et al, 2014;Tafuri et al, 2015;Bozzo et al, 2017;Taylor et al, 2016). Of these mechanisms, oxidative stress is considered the major factor in degeneration of motor neurons.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown nuclear translocation of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in a mutant TDP-43 transgenic cell model, but the expression of its downstream antioxidant enzyme is decreased (Duan et al, 2010;Wang et al, 2014). Thus, when cells are under oxidative stress, Nrf2 translocates from the cytoplasm to nuclei, and expression of the downstream antioxidant enzyme decreases.…”

Section: Introductionmentioning

confidence: 99%

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Effects of mutant TDP-43 on the Nrf2/ARE pathway and protein expression of MafK and JDP2 in NSC-34 cells

Tian

Che

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons and lacks an effective treatment. The disease pathogenesis has not been clarified at present. Pathological transactive response DNA-binding protein 43 (TDP-43) plays an important role in the pathogenesis of ALS. Nuclear translocation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is found in a mutant TDP-43 transgenic cell model, but its downstream antioxidant enzyme expression is decreased. To elucidate the specific mechanism of Nrf2/ARE (antioxidant responsive element) signaling dysfunction, we constructed an ALS cell model with human mutant TDP-43 using the NSC-34 cell line to evaluate the impact of the TDP-43 mutation on the Nrf2/ARE pathway. We found the nuclear translocation of Nrf2, but the expression of total Nrf2, cytoplasmic Nrf2, and downstream phase II detoxifying enzyme (NQO1) was decreased in NSC-34 cells transfected with the TDP-43-M337V plasmid. Besides, TDP-43-M337V plasmid-transfected NSC-34 cells were rounded with reduced neurites, shortened axons, increased levels of intracellular lipid peroxidation products, and decreased viability, which suggests that the TDP-43-M337V plasmid weakened the antioxidant capacity of NSC-34 cells and increased their susceptibility to oxidative damage. We further showed that expression of the MafK protein and the Jun dimerization protein 2 (JDP2) was reduced in TDP-43-M337V plasmid-transfected NSC-34 cells, which might cause accumulation of Nrf2 in nuclei but a decrease in NQO1 expression. Taken together, our results confirmed that TDP-43-M337V impaired the Nrf2/ARE pathway by reducing the expression of MafK and JDP2 proteins, and provided information for further research on the molecular mechanisms of TDP-43-M337V in ALS.

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Effect of the human SOD1-G93A gene on the Nrf2/ARE signaling pathway in NSC-34 cells

Cited by 22 publications

References 25 publications

ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling

Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

Effects of mutant TDP-43 on the Nrf2/ARE pathway and protein expression of MafK and JDP2 in NSC-34 cells

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