Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

Sun, Xiang; Xie, Linghai; Chen, Qian; Ye, Yongyi; Mao, Hengxu; Wang, Baoyan; Zhang, Huan; Zhang, Yizhou; He, Xiaozheng; Zhang, Shizhong

doi:10.1096/fj.201902967r

Cited by 14 publications

(11 citation statements)

References 62 publications

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“…Mounting evidence has shown that microglial NOX2 contributes to CNS OS and neuronal damage. NOX2-containing NADPH oxidases have emerged as a major source of OS in PD ( Gao et al, 2003a ; Qin et al, 2004 ; Wu et al, 2005 ; Kim et al, 2007 ; Gao et al, 2012 ; Marrali et al, 2018 ; Sun et al, 2020 ) ( Figure 5 ). NOX2 is expressed in several regions of the brain and various cell types, including neurons at the striatum ( McCann et al, 2008 ; Guemez-Gamboa et al, 2011 ), substantia nigra ( Zawada et al, 2011 ; Qin et al, 2013 ), and midbrain ( Qin et al, 2013 ), and is heavily expressed in microglia than in neurons and astroglia.…”

Section: The Sources Of Oxidative Stress In Parkinson’s Diseasementioning

confidence: 99%

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

et al. 2021

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Parkinson’s disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress (OS) has been implicated in the pathogenesis of PD. Genetic and environmental factors can produce OS, which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates activation of multiple protective genes, including heme oxygenase-1 (HO-1), which protects cells from OS. Nrf2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. Recently, a series of studies have reported that different bioactive compounds were shown to be able to activate Nrf2/antioxidant response element (ARE) and can ameliorate PD-associated neurotoxin, both in animal models and in tissue culture. In this review, we briefly overview the sources of OS and the association between OS and the pathogenesis of PD. Then, we provided a concise overview of Nrf2/ARE pathway and delineated the role played by activation of Nrf2/HO-1 in PD. At last, we expand our discussion to the neuroprotective effects of pharmacological modulation of Nrf2/HO-1 by bioactive compounds and the potential application of Nrf2 activators for the treatment of PD. This review suggests that pharmacological modulation of Nrf2/HO-1 signaling pathway by bioactive compounds is a therapeutic target of PD.

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Section: The Sources Of Oxidative Stress In Parkinson’s Diseasementioning

confidence: 99%

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

et al. 2021

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“…Mice were divided into four groups (15 per group), with each group receiving recombinant lentiviruses containing LV-oe-EGR1, LV-oe-NC (HanBio, Shanghai, China), miR-381 agomir, or agomir NC (GenePharma, Shanghai, China) at the SNc. The injection site at SNc was identified by the following stereotaxic coordinates: 3.08 mm posterior of the bregma, 1.01 mm from the midline, and 4.45 mm from the skull . Lentivirus (2 μL, 2 × 10 5 TU/μL) was injected with a microinjector at a rate of 0.25 μL/min.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective microRNA-381 Binds to Repressed Early Growth Response 1 (EGR1) and Alleviates Oxidative Stress Injury in Parkinson’s Disease

Guo

Gao

Zhao

2023

ACS Chem. Neurosci.

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As a common and disabling disease of the elderly, the standard therapies of Parkinson's disease (PD) fail to curb the ongoing neurodegeneration, thus calling for newer strategies. This work was conducted to examine the effect of microRNA-381 (miR-381) on oxidative stress injury to dopaminergic neurons in PD in vivo and in vitro. We established an in vivo mouse model of PD using 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) and an in vitro cell model of PD by treating dopaminergic neuron MN9D cells with 1-methyl-4-phenylpyridinium (MPP + ). It was established that miR-381 was poorly expressed in the substantia nigra pars compacta (SNc) of MPTP-lesioned mice. The motor function of MPTP-lesioned mice was evaluated in the presence of ectopic miR-381 expression, and oxidative stress and dopaminergic neuron injury were also characterized. Restoration of miR-381 was demonstrated to diminish oxidative stress and damage in dopaminergic neurons, accompanied by enhanced motor functions. Mechanistically, the putative binding sites of miR-381 were retrieved through the starBase database, and the luciferase activity assay confirmed that it bound to EGR1 and repressed its expression, which then upregulated the expression of PTEN and p53. The neuroprotective effects of miR-381 on the motor function and dopaminergic neuronal damage were counteracted by ectopic EGR1 expression. Together, this study indicates that the binding of miR-381 to EGR1 upregulates PTEN/p53 to alleviate PD, which provides novel insights for a neuroprotective mechanism in PD.

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“…AntagomiR-214-3p, lentivirus-packaged oe-HSF1 (LV-oe-HSF1), lentivirus-packaged oe-NFATc2 (LV-oe-NFATc2), and the corresponding controls were all provided by GenePharma (Shanghai, China) and stereotaxically injected into mice according to the previous method [34]. Briefly, after anaesthesia, the mouse was fixed on a stereotaxic apparatus (Render Biotech Co., Ltd, Shenzhen, China) and a hole was drilled for single unilateral injection at the following stereotactic coordinates: 3.0 mm anteroposterior from bregma; 1.2 mm mediolateral from bregma; 5.0 mm dorsoventral from bregma.…”

Section: Stereotaxic Injectionmentioning

confidence: 99%

HSF1 inhibits microglia activation to attenuate neuroinflammation via regulating miR-214-3p and NFATc2 in Parkinson’s disease

Liao¹,

Gu²,

Wang³

et al. 2023

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Parkinson's disease (PD) is characterized by microglia activation that leads to neuroinflammation. Heat shock transcription factor 1 (HSF1) is known to exert neuroprotective effects on neurodegenerative diseases. This study sought to analyse the role and mechanism of HSF1 in PD-induced neuroinflammation. The PD mouse models were established using 2,3,. Animal behaviour capacities and neuronal damage were assessed via behavioural tests, tyrosine hydroxylase (TH) staining, and immunofluorescence. Levels of HSF1, miR-214-3p, nuclear factor of activated T cells 2 (NFATc2), and neuroinflammatory factors were detected via Western blotting, and NFATc2 were tested via dual-luciferase or chromatin immunoprecipitation assays. Functional rescue experiments were designed to confirm the roles of miR-214-3p and NFATc2. HSF1 expression in brain tissues was downregulated upon MPTP treatment. HSF1 overexpression reduced motor deficits and loss of dopaminergic neurons, increased TH-positive neurons, and repressed neuroinflammation and microglia activation. Mechanically, HSF1 bound to the miR-214-3p promoter to increase its expression and inhibited NFATc2 transcription. miR-214-3p downregulation or NFATc2 overexpression reversed the inhibition of HSF1 overexpression on neuroinflammation and microglia activation. Overall, our findings unveiled the therapeutic role of HSF1 in PD-induced neuroinflammation and microglia activation via regulating miR-214-3p and NFATc2.

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Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

Cited by 14 publications

References 62 publications

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

Neuroprotective microRNA-381 Binds to Repressed Early Growth Response 1 (EGR1) and Alleviates Oxidative Stress Injury in Parkinson’s Disease

HSF1 inhibits microglia activation to attenuate neuroinflammation via regulating miR-214-3p and NFATc2 in Parkinson’s disease

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