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HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

机译：HDAC6可以挽救神经变性，并提供自噬与UPS之间的重要联系

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摘要

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.
机译：迟发性神经退行性疾病的一个显着特征是易损神经元中错误折叠的蛋白质积累。当错误折叠的蛋白质水平淹没了降解途径时，结果就是细胞毒性和神经变性。降解错误折叠蛋白的细胞机制包括泛素-蛋白酶体系统（UPS）（泛素化蛋白的主要非溶酶体降解途径）和自噬（溶酶体介导的降解途径）。长期以来，UPS和自噬一直被视为没有交叉点的互补降解系统。这种观点受到了两个观察到的相互作用的挑战，这些观察表明存在明显的相互作用：UPS的损伤在体外诱导自噬，而有条件的自噬在小鼠大脑中的敲除导致泛素阳性病理性神经变性。不知道自噬严格来说是并行降级系统，还是UPS受损时是否是补偿性降级系统。此外，如果这些系统之间存在补偿性相互作用，则分子链接是未知的。在这里我们表明，当果蝇中的UPS受损时，自噬可作为补偿性降解系统，而组蛋白脱乙酰基酶6（HDAC6）是一种与多泛素化蛋白相互作用的微管相关脱乙酰基酶，是这种补偿相互作用中必不可少的机制环节。我们发现，在神经退行性疾病脊髓小球性肌萎缩症的飞行模型中，对影响蛋白酶体的突变和对UPS损伤的响应引起代偿自噬。自噬以依赖于HDAC6的方式补偿UPS功能受损。此外，HDAC6的表达足以以自噬依赖性在体内挽救与UPS功能障碍相关的变性。这项研究表明自噬的损害（例如，与衰老或遗传变异有关）可能导致神经退行性变。更进一步，这些发现表明，通过增加HDAC6增强自噬可以干预神经退行性变。

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