Pandey Udai Bhan, Nie Zhiping, Batlevi Yakup, McCray Brett A, Ritson Gillian P, Nedelsky Natalia B, Schwartz Stephanie L, DiProspero Nicholas A, Knight Melanie A, Schuldiner Oren, Padmanabhan Ranjani, Hild Marc, Berry Deborah L, Garza Dan, Hubbert Charlotte C, Yao Tso-Pang, Baehrecke Eric H, Taylor J Paul
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Nature. 2007 Jun 14;447(7146):859-63. doi: 10.1038/nature05853.
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.
迟发性神经退行性疾病的一个显著特征是错误折叠蛋白在易损神经元中积累。当错误折叠蛋白的水平超过降解途径的能力时，结果就是细胞毒性和神经退行性变。降解错误折叠蛋白的细胞机制包括泛素-蛋白酶体系统（UPS），这是泛素化蛋白的主要非溶酶体降解途径，以及自噬，一种溶酶体介导的降解途径。长期以来，UPS和自噬一直被视为互补的降解系统，没有交集。这一观点受到了两项表明明显相互作用的观察结果的挑战：UPS功能受损在体外诱导自噬，并且在小鼠脑中条件性敲除自噬会导致伴有泛素阳性病理的神经退行性变。尚不清楚自噬是否严格来说是一个平行的降解系统，或者当UPS受损时它是否是一个补偿性降解系统；此外，如果这些系统之间存在补偿性相互作用，其分子联系尚不清楚。在这里，我们表明在果蝇中当UPS受损时自噬作为一个补偿性降解系统起作用，并且组蛋白去乙酰化酶6（HDAC6），一种与多聚泛素化蛋白相互作用的微管相关去乙酰化酶，是这种补偿性相互作用中必不可少的机制联系。我们发现，在影响蛋白酶体的突变以及神经退行性疾病脊髓延髓肌肉萎缩的果蝇模型中，响应UPS功能受损会诱导补偿性自噬。自噬以HDAC6依赖的方式补偿受损的UPS功能。此外，HDAC6的表达足以在体内以自噬依赖的方式挽救与UPS功能障碍相关的变性。这项研究表明自噬受损（例如，与衰老或基因变异相关）可能易导致神经退行性变。此外，这些发现表明有可能通过增强HDAC6以促进自噬来干预神经退行性变。
