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 10 publications

(5 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 43%

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

et al. 2022

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…ROS are also implicated in synaptic plasticity and homeostasis across species (78, 100, 109, 110). At the Drosophila NMJ, Semaphorin-Plexin signaling regulates cytoskeletal dynamics underlying homeostatic modulation of neurotransmitter release through Mical, which uses intrinsic redox potential to oxidize methionine residues in actin and promote depolymerization (111, 112).…”

Section: Discussionmentioning

confidence: 99%

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

Madhwani,

Sayied,

Ogata

et al. 2023

Preprint

View full text Add to dashboard Cite

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA modifying enzyme that methylates wobble uridines in specific tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Throughin vivostudies inDrosophila, we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory.ALKBH8null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss ofALKBH8or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth inALKBH8null animals, confirming oxidative stress as the underlying cause of dysregulation.ALKBH8animals also exhibit associative learning and memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA modification in redox homeostasis in the nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.Significance StatementtRNA modifying enzymes are emerging as important regulators of nervous system development and function due to their growing links to neurological disorders. Yet, their roles in the nervous system remain largely elusive. Throughin vivostudies inDrosophila, we link tRNA methyltransferase-regulated selenoprotein synthesis to synapse development and associative memory. These findings demonstrate the key role of tRNA modifiers in redox homeostasis during nervous system development and highlight the potential therapeutic benefit of antioxidant-based therapies for cognitive disorders linked to dysregulation of tRNA modification.

show abstract

JNK signalling regulates antioxidant responses in neurons

Cited by 10 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

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

Contact Info

Product

Resources

About