ArticleCell death & disease2017
Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 55 citations in OpenAlex.
- Mitophagy coordinates organelle crosstalk in health and diseases.Signal transduction and targeted therapy · 2026Review
- Review
- Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.Journal of neuropathology and experimental neurology · 2025Article
- The link between Mitochondria and Sarcopenia.Journal of physiology and biochemistry · 2025Review
- Inferring DNA methylation in non-skeletal tissues of ancient specimens.Nature ecology & evolution · 2025Article
- UAMC-3203 inhibits ferroptosis and promotes functional recovery in rats with spinal cord injury.Scientific reports · 2024Article
- Proteotoxic stress and the ubiquitin proteasome system.Seminars in cell & developmental biology · 2024Review
- Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence.Neurotoxicity research · 2024Review
- Andrographolide Inhibits Static Mechanical Pressure-Induced Intervertebral Disc Degeneration via the MAPK/Nrf2/HO-1 Pathway.Drug design, development and therapy · 2023Article
- Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons.The EMBO journal · 2022Article
- Article
- Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy.Frontiers in cellular and infection microbiology · 2021Review
- Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation.Frontiers in molecular biosciences · 2021Review
- Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.International journal of molecular sciences · 2020Review
- EIF3D promotes sunitinib resistance of renal cell carcinoma by interacting with GRP78 and inhibiting its degradation.EBioMedicine · 2019Article
- Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity.International journal of molecular sciences · 2019Review
- Proanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway.Oxidative medicine and cellular longevity · 2019Article
- SOD1Journal of cell science · 2018Article
- Dynamic metabolic patterns tracking neurodegeneration and gliosis following 26S proteasome dysfunction in mouse forebrain neurons.Scientific reports · 2018Article
- Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo.Translational neurodegeneration · 2018Article
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated.
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Registered trials
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