Naiki Hironobu, Okoshi Tadakazu, Ozawa Daisaku, Yamaguchi Itaru, Hasegawa Kazuhiro
Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Pathol Int. 2016 Apr;66(4):193-201. doi: 10.1111/pin.12394. Epub 2016 Mar 11.
Amyloidosis refers to a group of diseases with amyloid fibrils deposited in various organs and is classified into more than 30 diseases in humans based on the kind of amyloid protein. In order to elucidate the molecular pathogenesis of human amyloidosis, we studied the molecular mechanism of amyloid fibril formation in vitro. We first developed a novel fluorometric method to determine amyloid fibrils in vitro based on the unique characteristics of thioflavin T. We next proposed a nucleation-dependent polymerization model to explain the general mechanism of amyloid fibril formation in vitro. Based on this model, we characterized the biological molecular interactions that promote or inhibit amyloid fibril formation in vitro and developed models of pathological molecular environment for inducing human β2-microglobulin-related amyloidosis in long-term hemodialysis patients. We also proposed a novel and attractive cytotoxic mechanism of β2-microglobulin amyloid fibrils, that is, the disruption of endosomal/lysosomal membranes by endocytosed amyloid fibrils. These findings may be useful to elucidate the molecular pathogenesis of other kinds of human amyloidosis.
淀粉样变性是指一组淀粉样原纤维沉积于各种器官的疾病，根据淀粉样蛋白的种类，人类淀粉样变性可分为30多种疾病。为了阐明人类淀粉样变性的分子发病机制，我们研究了体外淀粉样原纤维形成的分子机制。我们首先基于硫黄素T的独特特性开发了一种新型荧光法来体外测定淀粉样原纤维。接下来，我们提出了一种依赖成核的聚合模型来解释体外淀粉样原纤维形成的一般机制。基于该模型，我们表征了促进或抑制体外淀粉样原纤维形成的生物分子相互作用，并建立了长期血液透析患者中诱导人β2微球蛋白相关淀粉样变性的病理分子环境模型。我们还提出了一种新颖且引人关注的β2微球蛋白淀粉样原纤维的细胞毒性机制，即内吞的淀粉样原纤维破坏内体/溶酶体膜。这些发现可能有助于阐明其他类型人类淀粉样变性的分子发病机制。
