JNK signalling regulates antioxidant responses in neurons

Ugbode, Chris; Garnham, Nathan; Fort-Aznar, Laura; Evans, Gareth J.; Chawla, Sangeeta; Sweeney, Sean T.

doi:10.1016/j.redox.2020.101712

Cited by 17 publications

(5 citation statements)

References 62 publications

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“…We found that MKK7, but not MKK4, participated in mechanical overloading-induced JNK activation. Although JNK signalling plays a key role in cell proliferation, differentiation and apoptosis in response to stress, the contributions of MKK7–JNK in cartilage ageing and OA progression in response to mechanical stress are not known 48 49. In the present study, we found that FBXW7 inhibition by excessive mechanical loading strongly elevated MKK7 expression and subsequently induced an increase in the JNK signal in chondrocytes, resulting in enhanced cell senescence.…”

Section: Discussionmentioning

confidence: 43%

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

et al. 2022

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ObjectivesTo investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression.MethodsF-box and WD repeat domain containing 7 (FBXW7) ubiquitin ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA sequencing was performed in articular cartilage from Fbxw7 knockout and control mice.ResultsMechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degenerationConclusionsFBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.

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Section: Discussionmentioning

confidence: 43%

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

et al. 2022

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“…We next asked whether functional PPARγ is also required for the therapeutic outcome of ASK1 inhibitors in proteasomal inhibition [ 49 ]. To this end, PPARγ in the liver was depleted by adenovirus, and mice were treated with selonsertib and bortezomib to monitor proteotoxicity ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

et al. 2021

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Incidence of hepatotoxicity following acute drug-induced proteasomal inhibition and development of chronic proteasome dysfunction in obesity and insulin resistance underscores the crucial importance of hepatic protein homeostasis albeit with an elusive molecular basis and therapeutic opportunities. Apart from lipotoxicity and endoplasmic reticulum (ER) stress, herein we report that hepatocytes are highly susceptible to proteasome-associated metabolic stress attune to altered redox homeostasis. Bortezomib-induced proteasomal inhibition caused severe hepatocellular injury independent of ER stress via proapoptotic Apoptosis Signal-regulating Kinase 1 (ASK1)- c-Jun N-terminal kinase (JNK1)- p38 signaling concomitant with inadequate peroxisome proliferator-activated receptor γ (PPARγ)- Nuclear factor erythroid 2-related factor 2 (Nrf2) -driven antioxidant response. Although inhibition of ASK1 rescued acute hepatotoxicity, hepatic depletion of PPARγ or its physiological activator pigment epithelium-derived factor (PEDF) further aggravated liver injury even under ASK1 inhibition, emphasizing that endogenous PPARγ driven antioxidant activity serves as a prerequisite for the favorable therapeutic outcome of ASK1 inhibition. Consequently, ASK1 inhibitor selonsertib and PPARγ agonist pioglitazone in pharmacological synergism ameliorated bortezomib-induced hepatotoxicity and significantly prolonged survival duration in mice. Moreover, we showed that proteasome dysfunction is associated with ASK1 activation and insufficient PPARγ/Nrf2-driven antioxidative response in a subset of human nonalcoholic steatohepatitis (NASH) patients and the preclinical NASH model. The latter remains highly responsive to the drug combination marked by revamped proteasomal activity and alleviated hallmarks of NASH such as steatosis, fibrosis, and hepatocellular death. We thus uncovered a pharmacologically amenable interdependent binodal molecular circuit underlying hepatic proteasomal dysfunction and associated oxidative injury.

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“…Recent work has also shown that in neurons, JNK is activated specifically by oxidative stress and activates c-jun containing AP-1 transcription factors independently of c-Fos. This specific c-jun activation results in an increased abundance of the antioxidant protein SRXN-1 [ 46 ]. Thus, the strong activation of c-jun we detected in 5xFAD lysates at 10 months could represent an attempt to counteract the decrease in GST.…”

Section: Discussionmentioning

confidence: 99%

JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model

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Giani

et al. 2023

Cells

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The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology.

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JNK signalling regulates antioxidant responses in neurons

Cited by 17 publications

References 62 publications

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model

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