A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy

Bott, Laura C.; Badders, Nisha M.; Chen, Ke-lian; Harmison, George G.; Bautista, Elaine; Shih, Charles C.-Y.; Katsuno, Masahisa; Sobue, Gen; Taylor, J. Paul; Dantuma, Nico P.; Fischbeck, Kenneth H.; Rinaldi, Carlo

doi:10.1093/hmg/ddw073

Cited by 60 publications

(56 citation statements)

References 53 publications

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“…For instance, the life expectancy of transgenic mice expressing human mutant SNCA A53T is largely increased when crossed with mice overexpressing NFE2L2 in astrocytes 69 and the NFE2L2 activator dimethyl fumarate, already in clinical use for multiple sclerosis, reduces SNCA toxicity 70 . Other NFE2L2 activators are being studied for alleviation of proteinopathies such as spinal and bulbar muscular atrophy 71 . Future work will be needed to determine if pharmacological induction of NFE2L2 may be a valid strategy to facilitate degradation of toxic proteins in the brain.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

et al. 2016

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Autophagy is a highly coordinated process that is controlled at several levels including transcriptional regulation. Here, we identify the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance in a mouse model of Alzheimer disease (AD) that reproduces impaired APP (amyloid β precursor protein) and human (Hs)MAPT/TAU processing, clearance and aggregation. We screened the chromatin immunoprecipitation database ENCODE for 2 proteins, MAFK and BACH1, that bind the NFE2L2-regulated enhancer antioxidant response element (ARE). Using a script generated from the JASPAR's consensus ARE sequence, we identified 27 putative AREs in 16 autophagy-related genes. Twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes by additional ChIP assays and quantitative RT-PCR on human and mouse cells after NFE2L2 activation with sulforaphane. Mouse embryo fibroblasts of nfe2l2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NFE2L2 expressing lentivirus, and impaired autophagy flux when exposed to hydrogen peroxide. NFE2L2-deficient mice co-expressing HsAPPV717I and HsMAPTP301L, exhibited more intracellular aggregates of these proteins and reduced neuronal levels of SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5 and GABARAPL1. Also, colocalization of HsAPPV717I and HsMAPTP301L with the NFE2L2-regulated autophagy marker SQSTM1/p62 was reduced in the absence of NFE2L2. In AD patients, neurons expressing high levels of APP or MAPT also expressed SQSTM1/p62 and nuclear NFE2L2, suggesting their attempt to degrade intraneuronal aggregates through autophagy. This study shows that NFE2L2 modulates autophagy gene expression and suggests a new strategy to combat proteinopathies.

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Section: Discussionmentioning

confidence: 99%

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

et al. 2016

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“…) induces broad antioxidant effects in HD mouse brain and ameliorates the neurological phenotype . The benefits of Nrf2 activation can be extended to other polyglutamine diseases such as spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) .…”

Section: Nrf2‐dependent Amelioration Of Age‐dependent Neurological Phmentioning

confidence: 99%

The role of Nrf2 signaling in counteracting neurodegenerative diseases

2018

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The transcription factor Nrf2 (nuclear factor‐erythroid 2 p45‐related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

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“…While inactivation of SKN-1A/Nrf1 is catastrophic, our results suggest that enhancing SKN-1A/Nrf1 activity can enhance proteasome function and increase resistance to proteotoxic insults. A recent study found that a pharmacological activator of Nrf1 is protective in a mouse model of spinal and bulbar muscular atrophy (Bott et al, 2016).…”

Section: Png-1/ngly1 and Skn-1a/nrf1 Control Proteostasismentioning

confidence: 99%

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

Lehrbach

Breen

Ruvkun

2019

Cell

120

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Graphical Abstract Highlights d PNGase edits glycosylated Asn residues of the SKN-1A transcription factor to Asp d These edits are required for SKN-1A to regulate proteasome subunit genes d Sequence-edited SKN-1A enhances proteostasis d Edits cause ER-targeted and cytosolic SKN-1 isoforms to regulate distinct genes SUMMARYThe proteasome mediates selective protein degradation and is dynamically regulated in response to proteotoxic challenges. SKN-1A/Nrf1, an endoplasmic reticulum (ER)-associated transcription factor that undergoes N-linked glycosylation, serves as a sensor of proteasome dysfunction and triggers compensatory upregulation of proteasome subunit genes. Here, we show that the PNG-1/NGLY1 peptide:N-glycanase edits the sequence of SKN-1A protein by converting particular N-glycosylated asparagine residues to aspartic acid. Genetically introducing aspartates at these N-glycosylation sites bypasses the requirement for PNG-1/NGLY1, showing that protein sequence editing rather than deglycosylation is key to SKN-1A function. This pathway is required to maintain sufficient proteasome expression and activity, and SKN-1A hyperactivation confers resistance to the proteotoxicity of human amyloid beta peptide. Deglycosylationdependent protein sequence editing explains how ER-associated and cytosolic isoforms of SKN-1 perform distinct cytoprotective functions corresponding to those of mammalian Nrf1 and Nrf2. Thus, we uncover an unexpected mechanism by which N-linked glycosylation regulates protein function and proteostasis.

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A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy

Cited by 60 publications

References 53 publications

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

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