Defective Autophagy in Parkinson's Disease: Role of Oxidative Stress
Defective Autophagy in Parkinson's Disease: Role of Oxidative Stress
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DOI：
10.1007/s12035-012-8318-1
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发表时间：
2012-12-01
影响因子：
5.1
通讯作者：
Mollace, Vincenzo
中科院分区：
文献类型：
--
作者：
Janda, Elzbieta;Isidoro, Ciro;Mollace, Vincenzo
帕金森病（PD）是神经退行性疾病的典型例子，氧化应激在其发病机制中起关键作用。PD的遗传易感因素，如Parkin，PTEN诱导的激酶1和DJ-1的突变以及暴露于农药和重金属，都有助于改变氧化还原平衡和黑质多巴胺能神经元的变性。自噬失调是一种溶酶体驱动的细胞器和蛋白质聚集体自我降解的过程，也与PD和PD相关突变有关，环境毒素对自噬失调。然而，实验证据表明，自噬在PD中的作用复杂而模糊，因为受损或异常上调的自噬通量已被证明会导致神经元丢失。最后，一般认为氧化应激是一种强烈的促自噬刺激。然而，来自神经生物学以及其他领域的一些证据表明活性氧和活性氮对自噬机制具有抑制作用。本文综述了支持PD中自噬失调的不同概念的科学证据，并试图调和氧化应激在自噬调节中的作用的明显矛盾的观点。自噬和氧化应激之间的复杂关系也被认为是在不断寻找新的PD治疗的背景下。
Parkinson's disease (PD) is a paradigmatic example of neurodegenerative disorder with a critical role of oxidative stress in its etiopathogenesis. Genetic susceptibility factors of PD, such as mutations in Parkin, PTEN-induced kinase 1, and DJ-1 as well as the exposure to pesticides and heavy metals, both contribute to altered redox balance and degeneration of dopaminergic neurons in the substantia nigra. Dysregulation of autophagy, a lysosomal-driven process of self degradation of cellular organelles and protein aggregates, is also implicated in PD and PD-related mutations, and environmental toxins deregulate autophagy. However, experimental evidence suggests a complex and ambiguous role of autophagy in PD since either impaired or abnormally upregulated autophagic flux has been shown to cause neuronal loss. Finally, it is generally believed that oxidative stress is a strong proautophagic stimulus. However, some evidence coming from neurobiology as well as from other fields indicate an inhibitory role of reactive oxygen species and reactive nitrogen species on the autophagic machinery. This review examines the scientific evidence supporting different concepts on how autophagy is dysregulated in PD and attempts to reconcile apparently contradictory views on the role of oxidative stress in autophagy regulation. The complex relationship between autophagy and oxidative stress is also considered in the context of the ongoing search for a novel PD therapy.