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• W3216769897 abstract "Although we can thoroughly describe individual neurodegenerative diseases from the molecular level through cell biology to histology and clinical presentation, our understanding of them and hence treatment gains have been depressingly limited, partly due to difficulty conceptualizing different diseases as variations within the same overarching pathological rubric. This review endeavors to create such rubric by knitting together the seemingly disparate phenomena of oxidative stress, dysregulated proteostasis, and neuroinflammation into a cohesive triad that highlights mechanistic connectivities. We begin by considering that brain metabolic demands necessitate careful control of oxidative homeostasis, largely through sulfur redox chemistry and glutathione (GSH). GSH is essential for brain antioxidant defense, but also for redox signaling and thus neuroinflammation. Delicate regulation of neuroinflammatory pathways (NFκB, MAPK-p38, and NLRP3 particularly) occurs through S-glutathionylation of protein phosphatases but also through redox-sensing elements like ASK1; the 26S proteasome and cysteine deubiquitinases (DUBs). The relationship amongst triad elements is underscored by our discovery that LanCL1 (lanthionine synthetase-like protein-1) protects against oxidant toxicity; mediates GSH-dependent reactivation of oxidized DUBs; and antagonizes the pro-inflammatory cytokine, tumor necrosis factor-α (TNFα). We highlight currently promising pharmacological efforts to modulate key triad elements and suggest nexus points that might be exploited to further clinical advantage." @default.
• W3216769897 created "2021-12-06" @default.
• W3216769897 creator A5012514269 @default.
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• W3216769897 creator A5031606152 @default.
• W3216769897 creator A5060933946 @default.
• W3216769897 creator A5066771924 @default.
• W3216769897 date "2022-01-01" @default.
• W3216769897 modified "2023-09-27" @default.
• W3216769897 title "At the intersection of sulfur redox chemistry, cellular signal transduction and proteostasis: A useful perspective from which to understand and treat neurodegeneration" @default.
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