Department of Physiological Sciences, Faculty of Natural Sciences, University of Stellenbosch, Stellenbosch 7600, South Africa.
DST/NRF Centre of Excellence in Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research Division of Molecular Biology & Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Prog Neurobiol. 2017 Jun;153:64-85. doi: 10.1016/j.pneurobio.2017.03.006. Epub 2017 Apr 3.
Neurodegenerative diseases are characterised by the presence of cytoplasmic and nuclear protein aggregates that result in toxicity and neuronal cell death. Autophagy is a physiological cellular process that engulfs primarily long-lived proteins as well as protein aggregates with subsequent cargo delivery for lysosomal degradation. The rate at which the material is degraded through autophagy is referred to as autophagic flux. Although we have progressed substantially in unravelling the role and regulation of the autophagy machinery, its dysfunction in pathology as well as its dynamic changes in the disease progression remains largely unclear. Furthermore, the magnitude of autophagic flux in neuronal subtypes is largely unknown and it is unclear to what extent the flux may be affected in distinct neurodegenerative disease states. In this review, we provide an introduction to autophagy in neuronal homeostasis and indicate how autophagy is currently measured and modulated for therapeutic purposes. We highlight the need not only to develop enhanced methodologies that target and assess autophagic flux precisely, but also to discern the dynamics of autophagy in different neuronal types and brain regions associated with the disease-specific pathology. Finally, we describe how existing and novel techniques for assessing autophagic flux could be implemented in order to distinguish between molecular defects associated with autophagic cargo and the machinery. In doing so, this review may provide novel insights in the assessment and control of autophagic flux that is aligned with the protein clearance dysfunction in neurodegenerative disorders.
神经退行性疾病的特征是存在细胞质和核蛋白聚集体，导致毒性和神经元细胞死亡。自噬是一种生理细胞过程，主要吞噬寿命长的蛋白质以及随后用于溶酶体降解的蛋白质聚集体。通过自噬降解物质的速度称为自噬通量。尽管我们在阐明自噬机制的作用和调节方面已经取得了很大进展，但自噬在病理学中的功能障碍及其在疾病进展中的动态变化在很大程度上仍不清楚。此外，神经元亚型中自噬通量的幅度在很大程度上是未知的，也不清楚在不同的神经退行性疾病状态下通量可能会受到多大影响。在这篇综述中，我们介绍了神经元稳态中的自噬，并指出了如何目前为治疗目的测量和调节自噬。我们强调不仅需要开发针对自噬通量进行精确靶向和评估的增强方法，还需要辨别与特定疾病病理学相关的不同神经元类型和脑区的自噬动力学。最后，我们描述了如何实施现有的和新的自噬通量评估技术，以便区分与自噬货物和机械有关的分子缺陷。这样，本综述可能会为神经退行性疾病中与蛋白质清除功能障碍相关的自噬通量的评估和控制提供新的见解。
