Loos Ben, Klionsky Daniel J, Wong Esther
Department of Physiological Sciences, Faculty of Science, University of Stellenbosch, Stellenbosch, 7600, South Africa.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
Prog Neurobiol. 2017 Sep;156:90-106. doi: 10.1016/j.pneurobio.2017.05.001. Epub 2017 May 11.
Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably.
神经细胞中有毒蛋白质聚集体的积累是神经元疾病和大脑衰老的一个标志。增强神经元监测以改善神经元蛋白质稳态的机制对促进神经元健康和预防与年龄相关的脑功能衰退具有直接影响。自噬是一种对神经元蛋白质质量控制至关重要的溶酶体降解途径。不同类型的自噬机制参与神经元中的蛋白质处理。巨自噬将自噬小泡中错误折叠和聚集的蛋白质靶向运送到溶酶体进行降解，而伴侣介导的自噬（CMA）则降解由伴侣蛋白递送到溶酶体的特定可溶性胞质蛋白。巨自噬和CMA功能障碍会导致与神经退行性变和衰老相关的蛋白质毒性和神经毒性。因此，增强或保留这两种自噬机制在延缓生理性和病理性神经元死亡方面具有显著益处。最近，调节代谢物酮体、通过热量限制控制能量摄入以及通过运动控制能量消耗的生活方式干预已被证明可增强自噬和大脑健康。然而，这些干预在多大程度上影响神经元自噬以促进大脑健康仍不清楚。在这里，我们综述了在神经退行性变背景下，酮体、热量限制和运动如何影响巨自噬和CMA的功能联系。同时对酿酒酵母进行评估，以揭示这种自噬对底物扰动反应的保守性质。通过这样做，我们为一种潜在的辅助治疗策略提供了新的见解和综合证据，该策略通过有利地控制巨自噬和CMA通量来干预神经退行性疾病中的神经元衰退。
