Elsevier

Redox Biology

Volume 11, April 2017, Pages 543-553
Redox Biology

Review article
Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

https://doi.org/10.1016/j.redox.2017.01.006Get rights and content
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Abstract

Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.

Abbreviations

α-SYN
alpha synuclein
β-TrCP
β-transducin repeat containing E3 ubiquitin protein ligase
amyloid beta
AD
Alzheimer's disease
ALS
amyotrophic lateral sclerosis
AMPK
AMP-activated protein kinase
ARE
antioxidant response element
ASK1
apoptosis-signal-regulating kinase 1
ATF-6
activating transcription factor 6
APP
amyloid precursor protein
CG islands
cytosine guanine islands
ChIP
chromatin immunoprecipitation
CJD
Creutzfeldt Jakob disease
CSF
cerebrospinal fluid
D3T
1,2-dithiole-3-thione
DMF
dimethyl fumarate
ER
endoplasmic reticulum
ERO1
sulfhydryl oxidase endoplasmic oxidoreductin 1
FOXO
forkhead box
GCLC
glutamate-cysteine ligase catalytic subunit
GCLM
glutamate-cysteine ligase modulatory subunit
GFP
green fluorescent protein
GLT-1
glutamate transporter 1
GPX
glutathione peroxidase
GR, GSR
glutathione reductase
GSH
glutathione (c-glutamyl-l-cysteinylglycine)
GSK-3
glycogen synthase kinase-3
GSSG
glutathione disulfide
GST
glutathione S-transferase
HD
Huntington's disease
Htt
huntingtin
HMOX1
heme oxygenase-1
IRE1
inositol-requiring kinase 1
JNK
c-Jun N-terminal kinase
KEAP1
kelch-like ECH-associated protein 1
MAPKs
mitogen-activated protein kinases
MPTP
1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
MEF
mouse embryonic fibroblasts
mTOR
mammalian target of rapamycin
NQO1
NAD(P)H:quinone oxidoreductase 1
NRF1
nuclear factor (erythroid-derived 2)-like 1
NRF2
nuclear factor (erythroid-derived 2)-like 2
LIR
LC3 interacting region
PERK
pancreatic ER eIF2α kinase
PD
Parkinson's disease
PDI
protein disulfide isomerase
PI3K
phosphatidyl inositol-3 kinase
PKA
protein kinase A
PKC
protein kinase C
PrP
prionic protein
PS1
presenilin 1
PRX
peroxiredoxin
ROS
reactive oxygen species
SFN
sulforaphane
SOD1
Cu/Zn-superoxide dismutase 1
TAK1
TGF-β-activated kinase 1
TFEB
transcription factor EB
UBA
ubiquitin associated domain
UPS
ubiquitin proteasome system
UPR
unfolded protein response
XBP1
X box-binding protein 1
γ-GCL
γ -glutamylcysteine synthetase
γGS
γ -glutamate cysteine synthetase
γGT
γ -glutamyl transpeptidase

Keywords

Neurodegenerative diseases
Unfolded protein response
Proteasome
Ubiquitin
Autophagy
Oxidative stress

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