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Review
. 2018 Oct;285(19):3576-3590.
doi: 10.1111/febs.14379. Epub 2018 Jan 29.

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Albena T Dinkova-Kostova  1   2 , Rumen V Kostov  1 , Aleksey G Kazantsev  3
Affiliations
Review

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Albena T Dinkova-Kostova et al. FEBS J. 2018 Oct.

Abstract

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.

Keywords: Nrf2 activator; neurodegeneration; neuroinflammation; neuroprotection; oxidative stress.

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Figures

Figure 1
Figure 1
Domain structure of Nrf2. The low affinity binding ‘DLG’ motif and the high affinity binding ‘ETGE’ motif in the N‐terminal Neh2 domain, through which Nrf2 binds to Keap1, are indicated. Also shown is the phosphodegron in the Neh6 domain through which, following phosphorylation by glycogen synthase kinase 3 (GSK3), Nrf2 binds to β‐transducin repeat‐containing protein (β‐TrCP).
Figure 2
Figure 2
Regulation of Nrf2 by ubiquitination and proteasomal degradation. Four known ubiquitin ligase systems mediate the degradation of Nrf2: Keap1, a substrate adaptor protein for Cul3/Rbx1‐based ubiquitin ligase and a cysteine‐based sensor for Nrf2 inducers; β‐TrCP, a substrate adaptor for Skp1‐Cul1/Rbx1‐based ubiquitin ligase, WDR23‐DDB1‐Cul4//Roc1‐based ubiquitin ligase, and Hrd1. Keap1‐mediated degradation requires that its cysteine sensors are in reduced state. β‐TrCP‐mediated degradation requires formation of a phosphodegron catalyzed by glycogen synthase kinase 3 (GSK3), which in turn requires phosphorylation by a priming kinase. Hrd1‐mediated degradation of Nrf2 occurs during ER stress.
Figure 3
Figure 3
Chemical structures of naturally occurring (A) and synthetic (B) Nrf2 activators with demonstrated efficacy in models of neurological conditions.
Figure 4
Figure 4
The multiple neuroprotective effects of Nrf2 and human pathologies, in which Nrf2 activation is envisioned to be therapeutically beneficial.
See this image and copyright information in PMC

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