Jackrel Meredith E, Shorter James
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA, USA.
Front Neurosci. 2017 Feb 28;11:99. doi: 10.3389/fnins.2017.00099. eCollection 2017.
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.
蛋白质错误折叠与多种神经退行性疾病有关，包括肌萎缩侧索硬化症、帕金森病、阿尔茨海默病和亨廷顿舞蹈症。这些疾病患者的一个共同特征是由错误折叠蛋白质组成的沉积物的积累。异常的蛋白质折叠可通过蛋白质功能的丧失或获得，或两者兼而有之，导致毒性。一种对抗这些疾病的有趣治疗方法是应用蛋白质重塑因子来解决这些错误折叠的构象，并使蛋白质恢复其天然折叠和功能。在这里，我们描述了蛋白质重塑因子在减轻神经退行性疾病中蛋白质错误折叠方面的应用。我们重点关注Hsp104、Hsp110/Hsp70/Hsp40、NMNAT和HtrA1，它们可以预防和逆转蛋白质聚集。虽然这些蛋白质重塑系统中的许多都非常有前景，但它们的活性可能受到限制。因此，对蛋白质重塑因子进行工程改造以增强其活性可能具有治疗价值。事实上，工程化的Hsp104变体可抑制动物模型中的神经退行性变，这为新型治疗方法和机制探针开辟了道路，有助于理解神经退行性疾病。
