The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling

Chew, Liang Yuh; Zhang, Heng; He, Jianzheng; Yu, Fengwei

doi:10.1016/j.celrep.2021.109466

Cited by 26 publications

(18 citation statements)

References 74 publications

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“…In a previous study, lovastatin treatment provides neuroprotection in the G2019S-induced PD model, also through the Akt/Nrf2 pathway ( Lin et al, 2016b ). As activation of neuronal Nrf2 plays a nonconventional role in promoting developmental dendrite pruning ( Chew et al, 2021 ), it remains interesting to further study the cell types that mediate the action of lovastatin. By genetically manipulating the G2019S fly model, we have shown that WGE-induced Nrf2 activation in glia but not in neurons protects dopaminergic neurons from degeneration and ameliorates impaired locomotion.…”

Section: Discussionmentioning

confidence: 99%

Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease

Lin

et al. 2021

eLife

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The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine-Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons, and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.

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Section: Discussionmentioning

confidence: 99%

Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease

Lin

et al. 2021

eLife

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“…NF-E2-relatedfactor2 (NRF2) plays an important role in regulating the homeostasis of cells and a key factor in oxidoreduction reaction (Zhang et al, 2016;Fan et al, 2017). Relevant studies have shown that when NRF2 is up-regulated in tumors, it is closely related to the poor prognosis of primary malignant brain tumors (Chew et al, 2021); the NRF2-Keap1 system regulates the expression of human antioxidant proteins, which is a typical antioxidant reaction pathway. Fe 2+ is regulated by NRF2.…”

Section: Iron Metabolism Affects the Ferroptosismentioning

confidence: 99%

Recent advances in ferroptosis and therapeutic strategies for glioblastoma

Lü²,

Zhang³

et al. 2023

Front. Mol. Biosci.

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Ferroptosis is an emerging form of cell death characterized by the over-accumulation of iron-dependent lipid peroxidation. Ferroptosis directly or indirectly disturbs glutathione peroxidases cycle through diverse pathways, impacting the cellular antioxidant capacities, aggravating accumulation of reactive oxygen species in lipid, and it finally causes oxidative overload and cell death. Ferroptosis plays a significant role in the pathophysiological processes of many diseases. Glioblastoma is one of the most common primary malignant brain tumors in the central nervous system in adults. Although there are many treatment plans for it, such as surgical resection, radiotherapy, and chemotherapy, they are currently ineffective and the recurrent rate is almost up to 100%. The therapies abovementioned have a strong relationship with ferroptosis at the cellular and molecular level according to the results reported by numerous researchers. The regulation of ferroptosis can significantly determine the outcome of the cells of glioblastoma. Thus ferroptosis, as a regulated form of programed cell death, has the possibility for treating glioblastoma.

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“…The expression of Sox14 also requires a cooperation between the chromatin remodelling factor Brahma (Brm) and the histone acetyltransferase CREB-binding protein (CBP), which leads to local histone acetylation at the sox14 locus [ 29 ]. Third, Sox14 in turn induces the expression of the F-actin disassembly factor Mical [ 27 , 30 ], the Cullin1-based E3 ubiquitin ligase complex [ 31 ] and activation of the metabolic regulator AMP-activated protein kinase [ 32 , 33 ] and the Nrf2-Keap1 pathway [ 34 ] to promote neuronal pruning. Although some key components of the ecdysone-induced signalling cascade have been identified, the transcriptional regulation machinery of neuronal pruning remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

Polycomb group genes are required for neuronal pruning in Drosophila

Lau

Yong

et al. 2023

BMC Biol

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Background Pruning that selectively eliminates unnecessary or incorrect neurites is required for proper wiring of the mature nervous system. During Drosophila metamorphosis, dendritic arbourization sensory neurons (ddaCs) and mushroom body (MB) γ neurons can selectively prune their larval dendrites and/or axons in response to the steroid hormone ecdysone. An ecdysone-induced transcriptional cascade plays a key role in initiating neuronal pruning. However, how downstream components of ecdysone signalling are induced remains not entirely understood. Results Here, we identify that Scm, a component of Polycomb group (PcG) complexes, is required for dendrite pruning of ddaC neurons. We show that two PcG complexes, PRC1 and PRC2, are important for dendrite pruning. Interestingly, depletion of PRC1 strongly enhances ectopic expression of Abdominal B (Abd-B) and Sex combs reduced, whereas loss of PRC2 causes mild upregulation of Ultrabithorax and Abdominal A in ddaC neurons. Among these Hox genes, overexpression of Abd-B causes the most severe pruning defects, suggesting its dominant effect. Knockdown of the core PRC1 component Polyhomeotic (Ph) or Abd-B overexpression selectively downregulates Mical expression, thereby inhibiting ecdysone signalling. Finally, Ph is also required for axon pruning and Abd-B silencing in MB γ neurons, indicating a conserved function of PRC1 in two types of pruning. Conclusions This study demonstrates important roles of PcG and Hox genes in regulating ecdysone signalling and neuronal pruning in Drosophila. Moreover, our findings suggest a non-canonical and PRC2-independent role of PRC1 in Hox gene silencing during neuronal pruning.

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The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling

Cited by 26 publications

References 74 publications

Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease

Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease

Recent advances in ferroptosis and therapeutic strategies for glioblastoma

Polycomb group genes are required for neuronal pruning in Drosophila

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