Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation.
Cell Death Dis
; 12(2): 218, 2021 02 26.
Article
em En
| MEDLINE
| ID: mdl-33637689
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.
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Base de dados:
MEDLINE
Assunto principal:
Prosencéfalo
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Fármacos Neuroprotetores
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Marcação de Genes
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Doença por Corpos de Lewy
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Fator 2 Relacionado a NF-E2
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Alfa-Sinucleína
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Sistemas CRISPR-Cas
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Hidroquinonas
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Neurônios
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article