Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease.
Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease.
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蛋白质重塑因子作为神经退行性疾病的潜在治疗方法。
DOI：
10.3389/fnins.2017.00099
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发表时间：
2017
影响因子：
4.3
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Jackrel ME;Shorter J
蛋白质错误折叠涉及许多神经退行性疾病，包括肌萎缩性侧索硬化症、帕金森病、阿尔茨海默病和亨廷顿病。患有这些疾病的患者的一个统一特征是由错误折叠的蛋白质组成的沉积物的积累。异常蛋白质折叠可通过蛋白质功能的丧失或获得或两者兼有而引起毒性。一个有趣的治疗方法，以对付这些疾病是蛋白质重塑因子的应用，以解决这些错误折叠的构象和返回的蛋白质到其天然的折叠和功能。在这里，我们描述了应用蛋白质重塑因子来减轻神经退行性疾病中的蛋白质错误折叠。我们重点关注Hsp 104、Hsp 110/Hsp 70/Hsp 40、NMNAT和HtrA 1，它们可以阻止和逆转蛋白质聚集。虽然许多这些蛋白质重塑系统是非常有前途的，但它们的活性可能是有限的。因此，工程蛋白质重塑因子，以提高其活性可能是有治疗价值的。事实上，工程化的Hsp 104变体抑制了动物模型中的神经退行性变，这为新的治疗方法和机制探针开辟了道路，以帮助理解神经退行性疾病。
Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function. Here, we describe the application of protein-remodeling factors to alleviate protein misfolding in neurodegenerative disease. We focus on Hsp104, Hsp110/Hsp70/Hsp40, NMNAT, and HtrA1, which can prevent and reverse protein aggregation. While many of these protein-remodeling systems are highly promising, their activity can be limited. Thus, engineering protein-remodeling factors to enhance their activity could be therapeutically valuable. Indeed, engineered Hsp104 variants suppress neurodegeneration in animal models, which opens the way to novel therapeutics and mechanistic probes to help understand neurodegenerative disease.