NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington's disease mouse model

Moretti, Daniele; Tambone, Sara; Cerretani, Mauro; Fezzardi, Paola; Missineo, Antonino; Sherman, Leticia-Toledo; Munoz-Sajuan, Ignacio; Harper, Steven J.; Dominquez, Celia; Pacifici, Robert E.; Tomei, Licia; Park, Larry; Bresciani, Alberto

doi:10.1016/j.freeradbiomed.2020.10.022

Cited by 36 publications

(21 citation statements)

References 31 publications

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“…In addition, these compounds alleviated body weight loss and ameliorated behavior disorder in a 3-Nitropropionic acid animal model of HD [164]. Recently, Moretti et al [165] designed and synthesized a novel non-acidic naphthalenederived compound that reversibly binds Keap1 and activates Nrf2. As a result, antioxidant enzyme expression is induced.…”

Section: Huntington's Diseasementioning

confidence: 99%

An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

Zgórzyńska

Dziedzic

Walczewska

2021

IJMS

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Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy.

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Section: Huntington's Diseasementioning

confidence: 99%

An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

Zgórzyńska

Dziedzic

Walczewska

2021

IJMS

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“…Moreover, given the putative regulatory role of NRF2 homeostatic response in ROS independent metabolic regulation (e.g., glutamine biogenesis, signal transduction) [ 23 , 31 , 65 ], these data also hint towards distinct compensatory mechanism(s) that could be a particular feature of different neuronal populations in a region (e.g., neurotransmitter phenotype, metabolic demands and adaptive response to stress). Specifically, the cellular difference in inducible NRF2 expression could play a significant role, as reflected by the studies showing that astrocytic NRF2 activation influences the redox homeostasis in neurons, and is a crucial factor in neuroprotection under oxidative stress [ 44 , 66 , 67 ]. Lastly, it is also plausible that the increased p-NRF2 (S40) nuclear immunostaining reflects a decreased nuclear export of NRF2 as a result of altered metabolic signaling in additional pathways (e.g., glycogen synthase kinase 3β, Fyn) [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Delaidelli

Richner

Jiang

et al. 2021

acta neuropathol commun

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Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

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“…Keap1 is a multi-domain repressor protein of the Kelch family, which binds to Nrf2 through the Cul3 ubiquitin ligase containing E3. Nrf2 is an important transcription factor that regulates cellular antioxidative stress and can promote the expression of a series of antioxidant protective proteins [47] . At the same time, it can coordinate many protective detoxi cation and anti-in ammatory genes, and synergistically improve the e ciency of the cellular defense system [48] .…”

Section: Discussionmentioning

confidence: 99%

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

Huang

Feng

et al. 2021

Preprint

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Background: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons that lead to brain dysfunction. Recurrent seizures or status epilepticus can cause irreversible brain damage. The JAK2-STAT3 signal transduction pathway is stimulated by cytokines and involved in various pathological processes including inflammation, apoptosis and immune regulation in central system diseases. Keap1/Nrf2 is an important anti-oxidative stress pathway, which can reduce the toxic effects of oxygen free radicals and endogenous toxins on neurons. Genistein (Gen) can modulate inflammation and neuronal apoptosis, and may thereby have antiepileptic effects. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. Methods: Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 hours post-epilepsy. Immunofluorescence staining was used to observe the number of mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. Results: Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs). Conclusions: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.

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NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington's disease mouse model

Cited by 36 publications

References 31 publications

An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

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