Department of Medical Biochemistry and Microbiology and the SciLifeLab, Uppsala University, Uppsala, Sweden.
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Adv Exp Med Biol. 2020;1221:631-645. doi: 10.1007/978-3-030-34521-1_25.
Amyloidosis refers to a group of diseases characterized by abnormal deposition of denatured endogenous proteins, termed amyloid, in the affected organs. Analysis of biopsy and autopsy tissues from patients revealed the presence of heparan sulfate proteoglycans (HSPGs) along with amyloid proteins in the deposits. For a long time, HSPGs were believed to occur in the deposits as an innocent bystander. Yet, the consistent presence of HSPGs in various deposits, regardless of the amyloid species, led to the hypothesis that these macromolecular glycoconjugates might play functional roles in the pathological process of amyloidosis. In vitro studies have revealed that HSPGs, or more precisely, the heparan sulfate (HS) side chains interact with amyloid peptides, thus promoting amyloid fibrillization. Although information on the mechanisms of HS participation in amyloid deposition is limited, recent studies involving a transgenic mouse model of Alzheimer's disease point to an active role of HS in amyloid formation. Heparanase cleavage alters the molecular structure of HS, and thus modulates the functional roles of HS in homeostasis, as well as in diseases, including amyloidosis. The heparanase transgenic mice have provided models for unveiling the effects of heparanase, through cleavage of HS, in various amyloidosis conditions.
淀粉样变性是一组疾病,其特征是在受影响的器官中异常沉积变性的内源性蛋白质,称为淀粉样物质。对患者活检和尸检组织的分析表明,在沉积物中存在硫酸乙酰肝素蛋白聚糖 (HSPG) 以及淀粉样蛋白。长期以来,HSPG 被认为是沉积物中的无辜旁观者。然而,各种沉积物中 HSPG 的一致存在,无论淀粉样物质的种类如何,都导致了这样的假设,即这些大分子糖缀合物可能在淀粉样变性的病理过程中发挥功能作用。体外研究表明,HSPG 或更确切地说是硫酸乙酰肝素 (HS) 侧链与淀粉样肽相互作用,从而促进淀粉样纤维形成。尽管关于 HS 参与淀粉样沉积的机制的信息有限,但最近涉及阿尔茨海默病转基因小鼠模型的研究表明 HS 在淀粉样形成中具有积极作用。肝素酶裂解改变 HS 的分子结构,从而调节 HS 在稳态以及包括淀粉样变性在内的疾病中的功能作用。肝素酶转基因小鼠为揭示 HS 通过肝素酶裂解在各种淀粉样变性条件下的作用提供了模型。