Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
J Neurosci. 2019 Sep 11;39(37):7291-7305. doi: 10.1523/JNEUROSCI.0625-19.2019. Epub 2019 Jul 29.
The oxidative metabolism of dopamine and consequent oxidative stress are implicated in dopaminergic neuronal loss, mediating the pathogenesis of Parkinson's disease (PD). The inducible detoxifying antioxidative enzyme Quinone oxidoreductase (NQO1) (NAD(P)H: quinone oxidoreductase 1), neuroprotective to counteract reactive oxidative species, is most prominent in the active stage of the disease and virtually absent at the end stage of the disease. However, the molecular mechanism dictating NQO1 expression oscillation remains unclear. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQO1 mutant displays more robust neuroprotective activity than WT NQO1 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both α-synuclein transgenic transgenic male and female mice elicited by the neurotoxin. Thus, our findings demonstrate that blockade of Akt-mediated NQO1 degradation may ameliorate PD pathogenesis. Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with the imbalance of oxidative metabolism of dopamine. Quinone oxidoreductase (NQO1), a potent antioxidant system, its expression levels are prominently increased in the early and intermediate stages of PD and disappeared in the end-stage PD. The molecular modification behavior of NQO1 after it is upregulated by oxidative stress in the early stage of PD, however, remains unclear. This study shows that Akt binds and phosphorylates NQO1 at T128 residue and promotes its ubiquitination and degradation, and Parkin acts as an E3 ligase in this process, which affects the antioxidant capacity of NQO1. This finding provides a novel molecular mechanism for NQO1 oscillation in PD pathogenesis.
多巴胺的氧化代谢和随之而来的氧化应激与多巴胺能神经元的丧失有关，介导帕金森病 (PD) 的发病机制。诱导型解毒抗氧化酶醌氧化还原酶 (NQO1)（NAD(P)H：醌氧化还原酶 1）对活性氧具有神经保护作用，在疾病的活跃阶段最为突出，而在疾病的终末期几乎不存在。然而，决定 NQO1 表达振荡的分子机制尚不清楚。在这里，我们表明 Akt 在 T128 残基上磷酸化 NQO1，并触发其多泛素化和蛋白酶体降解，从而消除其在 PD 中的抗氧化作用。Akt 以依赖于磷酸化的方式与 NQO1 结合。有趣的是，Akt，但不是 PINK1，作为 E3 连接酶，引发 NQO1 的磷酸化和多泛素化与 Parkin。不可磷酸化的 NQO1 突变体比 WT NQO1 更能有效地抑制活性氧并抑制 MPTP 诱导的多巴胺能细胞死亡，从而挽救神经毒素诱导的α-突触核蛋白转基因雄性和雌性小鼠的运动障碍。因此，我们的研究结果表明，阻断 Akt 介导的 NQO1 降解可能改善 PD 的发病机制。帕金森病 (PD) 中的多巴胺能神经退行性变与多巴胺氧化代谢失衡有关。醌氧化还原酶 (NQO1) 是一种有效的抗氧化系统，其表达水平在 PD 的早期和中期阶段显著增加，而在 PD 的晚期阶段消失。然而，NQO1 在 PD 早期氧化应激上调后的分子修饰行为仍不清楚。本研究表明，Akt 在 T128 残基上结合并磷酸化 NQO1，促进其泛素化和降解，Parkin 在这个过程中充当 E3 连接酶，这影响了 NQO1 的抗氧化能力。这一发现为 PD 发病机制中 NQO1 振荡提供了一个新的分子机制。
