Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation

• Published in: Cell death & disease 2021-02, Vol.12 (2), p.218-15, Article 218
• Main Authors: Baxter, Paul S., Márkus, Nóra M., Dando, Owen, He, Xin, Al-Mubarak, Bashayer R., Qiu, Jing, Hardingham, Giles E.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 14; 14/35; 38/109; 38/39; 38/91; 631/378/1689/1718; 631/378/2596/1308; 631/378/340; 631/378/87; 96; 96/95; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Antibodies; Antioxidants; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Death - drug effects; Cells, Cultured; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; CRISPR-Associated Protein 9 - genetics; CRISPR-Associated Protein 9 - metabolism; CRISPR-Cas Systems; Epigenetic Repression; Epigenetics; Female; Forebrain; Gene Targeting; gRNA; Hydroquinones - pharmacology; Immunology; Lewy Body Disease - genetics; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Lewy Body Disease - therapy; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Neurotoxicity; NF-E2-Related Factor 2 - agonists; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Prosencephalon - drug effects; Prosencephalon - metabolism; Prosencephalon - pathology; Protein folding; Proteostasis - drug effects; Synuclein; t-Butylhydroquinone; Transcription activation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03507-z

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.