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

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.

Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation

“…Recent studies demonstrate that Nrf2 activation contributes to the inhibition of microglial hyperactivation and protection against microgliosis-induced neuronal damage in the brain [7][8][9]. Nrf2 activation not only confers anti-oxidative effects but also modulates redox homoeostasis and regulates neuroinflammatory conditions in activated microglial cells [7,9,10,25,26].…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…. Recently, NRF2 was also found to regulate the expression of several proteasome subunits and autophagy genes, providing additional interest for its control of proteostasis (Pajares et al, 2015(Pajares et al, , 2016(Pajares et al, , 2017de la Vega et al, 2016).…”

“…8). Evidence pointing to pathologic ROS formation in proteinopathy, as well as NRF2 as regulator of proteasome and autophagy was provided in cellular and animal models (Pajares et al, 2017). Initially, it was reported that the autophagy cargo protein sequestosome 1 (SQSTM1) competes with NRF2 for binding to KEAP1.…”

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

“…Indeed, Nrf2 is first phosphorylated by the enzyme glycogen synthase kinase 3 (GSK-3β) at specific serine residues located in the Neh6 domain of Nrf2, generating a phosphorylated destruction motif called "phosphodegron." Hence, Nrf2 is recognized by the adapter protein β-TrCP that targets it for ubiquitination and subsequent 26S-mediated degradation [13,52]. Nrf2 can also be regulated through the protein synoviolin (Hdr1) E3 ubiquitin ligase [39], recently associated to the endoplasmic reticulum (ER) stress produced by misfolded protein accumulation.…”

“…Several works indicate that an optimal activity of Nrf2 is essential to protect cells against different stressors, and that its dysfunction is correlated with decreased tolerance to oxidative/chemical insults [8]. Therefore, alterations of the Nrf2 activity has been linked to the natural aging process [9,10] and to the pathogenesis of many human chronic diseases, including neurodegenerative [reviewed in [11][12][13] and cardiovascular diseases [14], fibrosis [15], inflammatory states [16], as well as with abnormalities in the susceptibility of tumor cells to chemo-and radio-therapy [reviewed in 17,18]. For these reasons, pharmacological/natural strategies that potentiate Nrf2 activity could be beneficial for preventing diseases in which oxidative stress exerts a pivotal role [7,[19][20][21].…”