Shorter James
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA.
Neurosignals. 2008;16(1):63-74. doi: 10.1159/000109760. Epub 2007 Dec 5.
Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer's and Parkinson's disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.
困扰人类的许多致命神经退行性疾病，包括阿尔茨海默病和帕金森病，都与特定蛋白质错误折叠成一种令人惊讶的通用纤维状构象（称为淀粉样蛋白）有关。在淀粉样纤维组装之前，许多蛋白质会形成一种常见的寡聚体构象，这种构象可能具有严重的细胞毒性。人们迫切寻求治疗创新方法，以安全地逆转这种异常的蛋白质聚集，并使蛋白质恢复正常功能。哺乳动物细胞是否具有任何此类内源性活性仍不清楚。相比之下，真菌、植物和细菌都表达Hsp104，一种蛋白质重塑因子，它与Hsp70伴侣系统协同作用，以分解聚集的蛋白质并恢复其功能。令人惊讶的是，淀粉样蛋白也可以是适应性的。在酵母中，Hsp104直接调节几种朊病毒蛋白的淀粉样蛋白生成，这可以赋予选择性优势。在这里，我回顾了Hsp104的作用方式，并展示了在与不同神经退行性淀粉样变性相关的蛋白质错误折叠事件中发挥Hsp104作用的努力。
