UK Dementia Research Institute at the University of Edinburgh, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
Cell Death Dis. 2021 Feb 26;12(2):218. 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.
许多神经退行性疾病都与神经元错误折叠的蛋白质积累有关，这表明需要促进蛋白质稳态的策略。在这里，我们表明，解除转录因子 Nrf2 的抑制作用（在早期神经元发育中被表观遗传关闭）可以防止蛋白质聚集体的积累。我们使用α-突触核蛋白积累和清除的范例发现，经典的亲电子 Nrf2 激活剂 tBHQ 可促进内源性 Nrf2 依赖性α-突触核蛋白在星形胶质细胞中的清除，但不能在皮质神经元中清除，皮质神经元没有 Nrf2 依赖性转录反应。此外，由于神经元 Nrf2 的抑制作用以及随之而来的较弱的抗氧化防御能力，亲电子 tBHQ 实际上通过非 Nrf2 依赖性 Jun 诱导引起氧化神经毒性。然而，我们发现，神经元 Nrf2 的表观遗传去抑制作用使它们能够对 Nrf2 激活剂做出反应，从而清除α-突触核蛋白。此外，使用 gRNA 靶向的 dCas9 为基础的转录激活复合物激活神经元 Nrf2 表达足以引发 Nrf2 依赖性α-突触核蛋白的清除。因此，针对前脑神经元中 Nrf2 的发育性关闭的逆转可能通过增强蛋白质稳态来改变神经退行性疾病的轨迹。
