van der Hilst J C H
Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, the Netherlands.
ScientificWorldJournal. 2011 Mar 7;11:641-50. doi: 10.1100/tsw.2011.64.
The amyloidoses are a group of life-threatening diseases in which fibrils made of misfolded proteins are deposited in organs and tissues. The fibrils are stable, insoluble aggregates of precursor proteins that have adopted an antiparallel beta-sheet structure. In type AA, or reactive, amyloidosis, the precursor protein of the fibrils is serum amyloid A (SAA). SAA is a 104-amino-acid protein that is produced in the liver in response to proinflammatory cytokines. Although the protein that is produced by the liver contains 104 amino acids, only the N-terminal 66-76 amino acids are found in amyloid fibrils. Furthermore, SAA has been shown to have an alpha-helical structure primarily. Thus, for SAA to be incorporated into an amyloid fibril, two processes have to occur: C-terminal cleavage and conversion into a beta-sheet. Only a minority of patients with elevated SAA levels develop amyloidosis. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in SAA, and the type of autoinflammatory syndrome. In the Hyper-IgD syndrome, amyloidosis is less prevalent than in the other autoinflammatory diseases. In vitro work has shown that the isoprenoid pathway influences amyloidogenesis by farnesylated proteins. Although many proteins contain domains that have a potential for self-aggregation, amyloidosis is only a very rare event. Heat shock proteins (HSPs) are chaperones that assist other proteins to attain, maintain, and regain a functional conformation. In this review, recent insights into the pathogenesis of amyloidosis are discussed, in addition to a new hypothesis for a role of HSPs in the pathogenesis of type AA.
淀粉样变性是一组危及生命的疾病，其中由错误折叠的蛋白质构成的纤维沉积在器官和组织中。这些纤维是前体蛋白质的稳定、不溶性聚集体，具有反平行β-折叠结构。在AA型或反应性淀粉样变性中，纤维的前体蛋白质是血清淀粉样蛋白A（SAA）。SAA是一种104个氨基酸的蛋白质，由肝脏响应促炎细胞因子而产生。尽管肝脏产生的这种蛋白质含有104个氨基酸，但在淀粉样纤维中仅发现N端的66 - 76个氨基酸。此外，SAA主要显示具有α-螺旋结构。因此，要使SAA掺入淀粉样纤维中，必须发生两个过程：C端切割和转化为β-折叠。只有少数SAA水平升高的患者会发生淀粉样变性。导致淀粉样变性风险的因素包括SAA升高的持续时间和程度、SAA中的多态性以及自身炎症综合征的类型。在高IgD综合征中，淀粉样变性的发生率低于其他自身炎症性疾病。体外研究表明，类异戊二烯途径通过法尼基化蛋白影响淀粉样蛋白生成。尽管许多蛋白质含有具有自我聚集潜力的结构域，但淀粉样变性只是一种非常罕见的情况。热休克蛋白（HSPs）是伴侣蛋白，可协助其他蛋白质获得、维持和恢复功能构象。在本综述中，除了关于HSPs在AA型发病机制中作用的新假说外，还讨论了对淀粉样变性发病机制的最新见解。
