PDF(Pubmed)
Abstract：
Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.
摘要：
遗传性甲状腺素运载蛋白淀粉样变性（hATTR）伴多发性神经病（以前称为家族性淀粉样多发性神经病（FAP））是一种地方性淀粉样变性，涉及蛋白质的有害聚集，最常见的是转甲状腺素蛋白（TTR），但有时也有载脂蛋白A-1或凝溶胶蛋白。hATTR似乎作为常染色体显性性状传播。已经鉴定出超过100个点突变,Val30Met替代是最常见的。然而，hATTR的发病机制和总体起源尚不清楚.这里,我们认为hATTR可能与有害金属接触有关。HATTR发病率在全球分布不均，三个最大的定义集群存在于日本，葡萄牙,和瑞典。这三个疫区也是古老的矿区，当地环境受到金属污染。有害金属有两种主要机制，摄取到组织和体液后，可以诱导hATTR。首先,金属可以直接影响表达，函数,和/或参与hATTR病理学的蛋白质的聚集。这种金属-蛋白质相互作用可能构成抗hATTR药物设计的分子靶标。第二,金属暴露可诱导HATTR相关基因突变，这可能发生在几代人之前。这两种机制可以并行发生。总之,在地球化学定义的区域，hATTR可能与金属暴露有关的可能性值得进一步关注。
