Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process
Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process
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DOI：
10.1128/mcb.01227-08
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发表时间：
2009-02-15
影响因子：
5.3
通讯作者：
Miura, Masayuki
中科院分区：
文献类型：
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作者：
Tonoki, Ayako;Kuranaga, Erina;Miura, Masayuki
未折叠或错误折叠的蛋白质的细胞内积累被认为有助于衰老和年龄相关的神经退行性疾病。然而，年龄依赖性蛋白质毒性和细胞蛋白质降解系统之间的联系仍然知之甚少。在这里，我们发现，26 S蛋白酶体的活性和丰度衰减与年龄，这是与受损的装配的26 S蛋白酶体与19 S调节颗粒（RP）和20 S蛋白酶体。在遗传获得性功能筛选中，我们将编码19S RP亚基的Rpn11表征为扩展聚谷氨酰胺诱导的进行性神经变性的抑制剂。Rpn 11过表达抑制了与年龄相关的26 S蛋白酶体活性的降低，从而延长了果蝇的寿命，抑制了泛素化蛋白的年龄依赖性积累。另一方面，Rpn 11功能的丧失导致26 S蛋白酶体活性降低和泛素化蛋白的过早年龄依赖性积累的早发性。它还导致寿命缩短和神经退行性表型增强。我们的研究结果表明，随着年龄的增长，保持26S蛋白酶体可以延长寿命，并抑制与年龄相关的神经退行性疾病的进展。
The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of neurodegenerative diseases.