Macroautophagy, a lysosomal pathway responsible for the turnover of organelles and long-lived proteins, has been regarded mainly as an inducible process in neurons, which is mobilized in states of stress and injury. New studies show, however, that macroautophagy is also constitutively active in healthy neurons and is vital to cell survival. Neurons in the brain, unlike cells in the periphery, are protected from large-scale autophagy induction because they can use several different energy sources optimally, receive additional nutrients and neurotrophin support from glial cells, and benefit from hypothalamic regulation of peripheral nutrient supplies. Due to its exceptional efficiency, constitutive autophagy in healthy neurons proceeds in the absence of easily detectable autophagic vacuole intermediates. These intermediates can accumulate rapidly, however, when late steps in the autophagic process are blocked. Autophagic vacuoles also accumulate abnormally in affected neurons of several major neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, where they have been linked to various aspects of disease pathogenesis including neuronal cell death. The build-up of autophagic vacuoles in these neurological disorders and others may reflect either heightened autophagy induction, impairment in later digestive steps in the autophagy pathway, or both. Determining the basis for AV accumulation is critical for understanding the pathogenic significance of autophagy in a given pathologic state and for designing possible therapies based on modulating autophagy. In this review, we discuss the special features of autophagy regulation in the brain, its suspected roles in neurodevelopment and plasticity, and recent progress toward understanding how dysfunctional autophagy contributes to neurodegenerative disease.

译文

:巨噬细胞吞噬,一种负责细胞器和长寿蛋白质更新的溶酶体途径,主要被认为是神经元的诱导过程,在压力和损伤状态下被动员。然而,新研究表明,巨噬细胞自噬在健康神经元中也具有组成性活性,对细胞存活至关重要。与周围的细胞不同,大脑中的神经元可以免受大规模自噬的诱导,因为它们可以最佳地利用几种不同的能源,可以从神经胶质细胞中获得更多的营养和神经营养蛋白支持,并受益于下丘脑对周围营养供应的调节。由于其出色的效率,健康神经元中的组成型自噬在缺乏易于检测的自噬液泡中间体的情况下进行。但是,当自噬过程的后期步骤被阻滞时,这些中间体会迅速积累。自噬空泡还在几种主要的神经退行性疾病(包括阿尔茨海默氏病和帕金森氏病)的受影响神经元中异常蓄积,它们与疾病发病机制的各个方面(包括神经元细胞死亡)相关。在这些神经系统疾病和其他神经系统疾病中,自噬泡的形成可能反映了自噬诱导的增强,自噬途径中以后消化步骤的损伤或两者兼而有之。确定AV积累的基础对于理解给定病理状态下自噬的致病意义以及基于调节自噬设计可能的治疗方法至关重要。在这篇综述中,我们讨论了大脑中自噬调节的特殊功能,其在神经发育和可塑性中的可疑作用,以及了解功能失调的自噬如何导致神经退行性疾病的最新进展。

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