Reductive stress promotes protein aggregation and impairs neurogenesis
| Autor: | Qin Wang, Namakkal S. Rajasekaran, Kishore Kumar S Narasimhan, Thomas van Groen, Sandhya Sundaram, Federica del Monte, Goutam Karan, Asokan Devarajan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
GSSG Oxidized glutathione GCLM γ-Glutamyl Cysteine Ligase Metabolic subunit Clinical Biochemistry H2O2 Hydrogen peroxide ERO1α Endoplasmic reticulum oxidoreductase 1 alpha medicine.disease_cause Biochemistry PDI Protein disulfide isomerase 0302 clinical medicine lcsh:QH301-705.5 OS Oxidative stress lcsh:R5-920 Nrf2 Nuclear factor (erythroid-derived-2)-like 2 Chemistry NQO1 NADPH quinone oxidoreductase 1 Neurogenesis PQC Protein quality control ER Endoplasmic Reticulum Endoplasmic Reticulum Stress Glutathione Cell biology RS Reductive stress SEM Standard Error of Mean GCLC γ-Glutamyl Cysteine Ligase Catalytic subunit GSR Glutathione-S-reductase lcsh:Medicine (General) ER stress Oxidation-Reduction Research Paper Cell signaling Neurite DHE Dihydro-ethidium ERP44/72 Endoplasmic Reticulum Protein 44/72 SF Sulforaphane GPX1 Glutathione peroxidase 1 GRP78/94 Glucose-regulated protein 78/94 Reductive stress CHOP CCAAT-enhancer-binding protein homologous protein MTT 3-[4 5-dimethylthiazole-2-yl]-2 5-diphenyltetrazolium bromide Nrf2 Proteotoxicity GSH Reduced glutathione 03 medical and health sciences Protein Aggregates RA Retinoic acid medicine GSK3β Glycogen Synthase Kinase 3 beta UPR Unfolded protein response Endoplasmic reticulum Organic Chemistry Oxidative Stress 030104 developmental biology Proteostasis lcsh:Biology (General) Unfolded protein response 030217 neurology & neurosurgery Oxidative stress ROS Reactive oxygen species |
| Zdroj: | Redox Biology Redox Biology, Vol 37, Iss, Pp 101739-(2020) |
| ISSN: | 2213-2317 |
| Popis: | Redox homeostasis regulates key cellular signaling in both physiology and pathology. While perturbations result in shifting the redox homeostasis towards oxidative stress are well documented, the influence of reductive stress (RS) in neurodegenerative diseases and its mechanisms are unknown. Here, we postulate that a redox shift towards the reductive arm (through the activation of Nrf2 signaling) will damage neurons and impair neurogenesis. In proliferating and differentiating neuroblastoma (Neuro 2a/N2a) cells, sulforaphane-mediated Nrf2 activation resulted in increased transcription/translation of antioxidants and glutathione (GSH) production along with significantly declined ROS in a dose-dependent manner leading to a reductive-redox state (i.e. RS). Interestingly, this resulted in endoplasmic reticulum (ER) stress leading to subsequent protein aggregation/proteotoxicity in neuroblastoma cells. Under RS, we also observed elevated Tau/α-synuclein and their co-localization with other protein aggregates in these cells. Surprisingly, we noticed that acute RS impaired neurogenesis as evidenced from reduced neurite outgrowth/length. Furthermore, maintaining the cells in a sustained RS condition (for five consecutive generations) dramatically reduced their differentiation and prevented the formation of axons (p Graphical abstract Image 1 Highlights • Sulforaphane promotes Nrf2/Antioxidant signaling and establishes reductive stress (RS) in Neuroblastoma (N2a) cells. • RS diminishes basal ROS and impairs protein folding signals to induce protein aggregation and proteotoxicity. • Acute, as well as chronic RS conditions impair neurogenesis. • RS-mediated proteotoxic insult inhibits differentiation of N2a cells through GSK3β activation and TAU hyper-phosphorylation. • Rescuing N2a cells from RS reactivates neurogenesis through suppressing the pathologic GSK3β/Tau cascade. |
| Databáze: | OpenAIRE |
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