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

Article ID	Journal	Published Year	Pages	File Type
8287073	Redox Biology	2017	11 Pages	PDF

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.

Keywords

AMPK PDI DMF PI3K Jnk MEF GFP Nrf2 GSH GST Aβ GPX mTOR GSSG SFN α-Syn APP pKa MPTP GLT-1 PS1 UPR PKC IRE1 XBP1 PrP SOD1 GSK-3 Heme oxygenase-1 NRF1 htt ASK1 HMOX1 NQO1 CJD TAK1 GCLC γGT TFEB GCLM PRX D3T UBA 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine LC3 interacting region β-TrCP phosphatidyl inositol-3 kinase Ero1 1,2-Dithiole-3-thione γ-GCL ubiquitin associated domain TGF-β-activated kinase 1 inositol-requiring kinase 1 ATF-6 Creutzfeldt Jakob disease AMP-activated protein kinase keap1 c-Jun N-terminal kinase MAPKs NAD(P)H:quinone oxidoreductase 1 presenilin 1 ROS Autophagy amyotrophic lateral sclerosis chromatin immunoprecipitation amyloid beta LIR Alzheimer's disease ALS Huntington's disease Neurodegenerative diseases Parkinson's disease Oxidative stress forkhead box dimethyl fumarate Sulforaphane Ubiquitin proteasome system Alpha synuclein endoplasmic reticulum Transcription factor EB antioxidant response element nuclear factor (erythroid-derived 2)-like 2 FoxO activating transcription factor 6 Cerebrospinal fluid CSF mouse embryonic fibroblasts Huntingtin mammalian target of rapamycin ARE Unfolded protein response Proteasome protein disulfide isomerase green fluorescent protein Kelch-like ECH-associated protein 1 amyloid precursor protein protein kinase A Protein kinase C Peroxiredoxin PERK CHiP glutamate-cysteine ligase catalytic subunit mitogen-activated protein kinases glutathione S-transferase glutathione disulfide glutathione reductase glutathione peroxidase glutamate transporter 1 glycogen synthase kinase-3 Reactive oxygen species UPS Ubiquitin