Abstract
Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut-off in early neuronal development, can prevent protein aggregate accumulation. Using a paradigm of α-synuclein accumulation and clearance, we find that the classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2-dependent α-synuclein clearance in astrocytes, but not cortical neurons, which mount no Nrf2-dependent transcriptional response. Moreover, due to neuronal Nrf2 shut-off and consequent weak antioxidant defences, electrophilic tBHQ actually induces oxidative neurotoxicity, via Nrf2-independent Jun induction. However, we find that epigenetic de-repression of neuronal Nrf2 enables them to respond to Nrf2 activators to drive α-synuclein clearance. Moreover, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is sufficient to trigger Nrf2-dependent α-synuclein clearance. Thus, targeting reversal of the developmental shut-off of Nrf2 in forebrain neurons may alter neurodegenerative disease trajectory by boosting proteostasis.
Highlights
Introduction The transcription factorNrf[2] is a widely expressed stress-responsive regulator of several aspects of homoeostatic physiology
Activation of endogenous Nrf[2] can drive α-synuclein clearance in astrocytes but not neurons To establish whether activators of endogenous neuronal
We found that tBHQ treatment (10 μM) significantly reduced α-synuclein accumulation in astrocytes, but failed to reduce α-synuclein in cortical neurons (Fig. 1a–d)
Summary
Introduction The transcription factorNrf[2] is a widely expressed stress-responsive regulator of several aspects of homoeostatic physiology. Nrf[2] activity can be manipulated by conventional overexpression or knock-down, and endogenous Nrf[2] dependent gene expression can be activated by disrupting the ability of Keap[1] to promote Nrf[2] degradation, using a number of small molecules, most commonly acting via the electrophilic modification of redox sensitive Keap[1] cysteine residues[1,5,6] This pharmacological activation approach has been shown in pancreatic ß-cells, mouse embryonic fibroblasts and breast cancer cells to repress cytotoxicity and unfolded protein response (UPR) over-activation in response to ER stress inducers, at least in part through maintenance of ER redox balance and disulphide chemistry[7,8,9]. Nrf[2] boosts the macroautophagy pathway, as evidenced from studies in HeLa cells and MEFs10,11
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