1. Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation.
- Author
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Baxter PS, Márkus NM, Dando O, He X, Al-Mubarak BR, Qiu J, and Hardingham GE
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, CRISPR-Associated Protein 9 genetics, CRISPR-Associated Protein 9 metabolism, Cell Death drug effects, Cells, Cultured, Clustered Regularly Interspaced Short Palindromic Repeats, Coculture Techniques, Epigenetic Repression, Female, Lewy Body Disease genetics, Lewy Body Disease metabolism, Lewy Body Disease pathology, Male, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Neurons drug effects, Neurons pathology, Prosencephalon metabolism, Prosencephalon pathology, Proteostasis drug effects, alpha-Synuclein genetics, Mice, CRISPR-Cas Systems, Gene Targeting, Hydroquinones pharmacology, Lewy Body Disease therapy, NF-E2-Related Factor 2 agonists, Neurons metabolism, Neuroprotective Agents pharmacology, Prosencephalon drug effects, alpha-Synuclein metabolism
- 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.
- Published
- 2021
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