Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease
Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease
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DOI：
10.1016/j.mcn.2019.103413
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发表时间：
2019-12-01
影响因子：
3.5
通讯作者：
Thomas, Bobby
中科院分区：
文献类型：
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作者：
Kaidery, Navneet Ammal;Ahuja, Manuj;Thomas, Bobby
寻找帕金森氏病(PD)等神经退行性疾病的最终治疗方法几乎没有取得什么成功。线粒体功能障碍和氧化应激升高先于帕金森病患者中脑产生多巴胺的神经元的特征性丢失。大多数PD病例被归类为散发性(SPD)，病因不明，而少数基因的突变导致称为家族性(FPD)的单基因形式。SPD和FPD都以蛋白质病变和线粒体功能障碍为特征，导致氧化应激增加。这些病理生理机制造成了相互补充的恶性循环，最终导致神经元死亡。铁积累和多巴胺氧化的影响增加了线粒体氧化应激和受影响的凋亡途径的额外维度。NRF2是一种氧化还原敏感的转录因子，它调节与异物解毒相关的抗氧化酶和蛋白质的基础和诱导表达。然而，最近的进展表明，Nrf2在调节与炎症反应、代谢途径、蛋白质稳态、铁管理和线粒体相关的基因方面具有多方面的作用！生物能量学。在这里，我们综述了线粒体和氧化应激在帕金森病发病机制中的作用，以及Nrf2信号和线粒体功能在帕金森病中的潜在串扰。我们还提出了安全激活Nrf2通路以阻止PD患者神经变性进展的治疗方法的开发。
Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has met with little success. Mitochondrial dysfunction and elevated oxidative stress precede characteristic loss of dopamine-producing neurons from the midbrain in PD. The majority of PD cases are classified as sporadic (sPD) with an unknown etiology, whereas mutations in a handful of genes cause monogenic form called familial (fPD). Both sPD and fPD is characterized by proteinopathy and mitochondrial dysfunction leading to increased oxidative stress. These pathophysiological mechanisms create a vicious cycle feeding into each other, ultimately tipping the neurons to its demise. Effect of iron accumulation and dopamine oxidation adds an additional dimension to mitochondrial oxidative stress and apoptotic pathways affected. Nrf2 is a redox-sensitive transcription factor which regulates basal as well as inducible expression of antioxidant enzymes and proteins involved in xenobiotic detoxification. Recent advances, however, shows a multifaceted role for Nrf2 in the regulation of genes connected with inflammatory response, metabolic pathways, protein homeostasis, iron management, and mitochondria! bioenergetics. Here we review the role of mitochondria and oxidative stress in the PD etiology and the potential crosstalk between Nrf2 signaling and mitochondrial function in PD. We also make a case for the development of therapeutics that safely activates Nrf2 pathway in halting the progression of neurodegeneration in PD patients.