Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract
Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract
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DOI：
10.1074/jbc.275.12.8772
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发表时间：
2000-03-24
影响因子：
4.8
通讯作者：
Sobue, G
中科院分区：
文献类型：
--
作者：
Kobayashi, Y;Kume, A;Sobue, G
脊髓和延髓肌萎缩症（SBMA）是由聚谷氨酰胺扩张引起的一组人类遗传性神经退行性疾病之一。我们之前已经证明，SBMA 基因产物（雄激素受体蛋白）具有毒性，并且在截短时会聚集。热休克蛋白充当分子伴侣，识别错误折叠的蛋白质（聚集体）并使其复性。因此，我们评估了多种伴侣在 SBMA 培养神经元细胞模型中的作用。在 SBMA 培养的神经元细胞模型中，伴侣蛋白的过度表达会不同程度地减少聚集体形成并抑制细胞凋亡，具体取决于伴侣蛋白及其组合。 Hsp70 和 Hsp40 的组合在减少聚集体形成和提供细胞保护方面是最有效的伴侣，这反映出 Hsp70 和 Hsp40 在伴侣突变和失能蛋白中共同作用。尽管 Hdj2/Hsdj 伴侣先前已被报道可抑制扩展的聚谷氨酰胺束形成的聚集体，但 Hsdj/Hdj2 在我们的系统中几乎没有显示出效果。这些发现表明伴侣可能是CAG重复疾病发生的关键因素之一，并表明增加表达水平或增强伴侣的功能将为CAG重复疾病的治疗提供途径。
Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. We have previously demonstrated that the SBMA gene product, the androgen receptor protein, is toxic and aggregates when truncated. Heat shock proteins function as molecular chaperones, which recognize and renaturate misfolded protein (aggregate). We thus assessed the effect of a variety of chaperones in a cultured neuronal cell model of SBMA. Overexpression of chaperones reduces aggregate formation and suppresses apoptosis in a cultured neuronal cell model of SBMA to differing degrees depending on the chaperones and their combinations. Combination of Hsp70 and Hsp40 was the most effective among the chaperones in reducing aggregate formation and providing cellular protection, reflecting that Hsp70 and Hsp40 act together in chaperoning mutant and disabled proteins. Although Hdj2/Hsdj chaperone has been previously reported to suppress expanded polyglutamine tract-formed aggregate, Hsdj/Hdj2 showed little Effect in our system. These findings indicate that chaperones may be one of the key factors in the developing of CAG repeat disease and suggested that increasing expression level or enhancing the function of chaperones will provide an avenue for the treatment of CAG repeat disease.