RESEARCH ON THE MOLECULAR MECHANISM UNDERLYING THE TRANSMISSION PHENOMENON IN AMYLOIDOSES INVOLVING HUMAN NEUROLOGICAL SYSTEMS

淀粉样变性是一组由蛋白质结构紊乱引起的疾病，其中通常可溶的蛋白质作为由β-折叠片组成的不溶性淀粉样原纤维沉积在组织中。成核依赖性聚合或播种被假定为包括peon疾病在内的几种淀粉样变性中纤维形成的模型。已报道在几种类型的淀粉样变性中，例如朊病毒病、小鼠AApoAII淀粉样变性和小鼠淀粉样蛋白AA淀粉样变性，通过给予淀粉样蛋白原纤维加速淀粉样蛋白沉积和疾病的传染性。甲状腺素运载蛋白（TTR）相关的家族性淀粉样多发性神经病（FAP）的家族表现出遗传预测，TTR-淀粉样蛋白沉积在连续几代的较早年龄。值得注意的是，受影响的母亲的后代似乎比受影响的父亲的后代更容易期待。预测FAT的分子基础仍有待确定。我们假设 ...更多信息 FAP的预期可能是由TTR-淀粉样纤维从受影响的母亲到他们的后代，本研究的目的是检验这一hypothes.First，我们调查了乳腺组织的3名女性患者FAP谁被证明有淀粉样蛋白沉积在腹部脂肪组织。刚果红染色阳性的淀粉样蛋白沉积量不一，乳腺淀粉样蛋白沉积的70年代与患者临床70年代几乎成正比。淀粉样蛋白沉积主要见于乳腺的上皮部分，围绕形成肺泡的腺上皮细胞。此外，在一些肺泡中，肺泡上皮细胞分离，使得沉积的淀粉样蛋白直接邻近或突出到肺泡腔中。我们认为，乳腺中的淀粉样蛋白沉积，特别是那些在腺腔中直接与乳汁接触的淀粉样蛋白沉积，可能是淀粉样蛋白纤维的来源，这些纤维可以传播给母乳喂养的后代。我们询问是否施用从具有变异TTR的FAP患者提取的TTR-淀粉样纤维（ATTR）（Val 30 Met）将加速表达负责FAP的人突变ttr基因的转基因小鼠中的ATTR沉积。根据Pras及其同事的研究，ATTR原纤维作为水悬液组分从一名日本患者的尸检心脏中分离出来，该患者患有FAP杂合子，具有正常和Va 130 Met变异TTR。将分离的淀粉样纤维注射到8-13月龄转基因小鼠的尾静脉中。将等体积的DW注射到相同年龄的转基因小鼠中作为对照。4个月或12个月后，用乙醚麻醉后处死转基因小鼠。切除各种组织并进行病理学检查。注射后12个月，在注射TTR的所有5只转基因小鼠的各种组织（食管、胃、肠、肺、肝、肾、心脏）中观察到嗜酸性淀粉样蛋白沉积，而在注射DW的5只对照转基因同窝小鼠中均未检测到沉积。该结果清楚地表明，从FAP患者的心脏提取的ATTR原纤维在体内发挥淀粉样变性加速活性。在免疫组化分析中，所有5只注射ATTR的转基因小鼠中的淀粉样蛋白沉积物仅与抗小鼠AApoAII抗体反应，而不与抗人TTR抗体反应。这些结果表明，施用人ATTR原纤维确实加速了小鼠AApoAII淀粉样蛋白的沉积，而不是相同的人ATTR。少

Amyloidoses are a group of diseases caused by the structural disorder of proteins in which normally soluble proteins are deposited in tissues as insoluble amyloid fibrils made up of β-pleated sheets. Nucleation dependent polymerization or seeding is postulated as a model of fibril formation in several kinds of amyloidoses including peon diseases. Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of the disease have been reported in several types of amyloidoses, such as prion diseases, mouse AApoAII amyloidosis and mouse amyloid AA amyloidosis. Families with transthyretin (TTR)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR-amyloid depositing at an earlier age in successive generations. Notably, descendents of affected mothers appear to be more prone to anticipation than descendents of affected fathers. The molecular bases of anticipation in FAT have remained to be determined. We hypothesized that th … More e anticipation in FAP may be caused by transmission of TTR-amyloid fibrils from affected mothers to their offspring, and the purpose of this study was to examine this hypothesis.First, we investigated mammary gland tissues of three female patients with FAP who were proven to have amyloid deposition in abdominal fat tissues. There was a variable amount of amyloid deposition positively stained with Congo red, and the seventies of the amyloid deposition in mammary glands were almost proportional to the clinical seventies of the patients. Amyloid deposition was seen mainly in the epithelial portion of the mammary gland, surrounding the glandular epithelial cells that form the alveoli. Furthermore, in some alveoli, alveolar epithelial cells were detached so that deposited amyloid was directly adjacent to or projecting into the lumen of the alveoli. We consider that amyloid deposits in mammary glands, especially those that directly come in contact with milk in the glandular lumens, may be the source of amyloid fibrils that could be transmitted to breast-fed offspringSecondly, we asked if administration of TTR-amyloid fibrils (ATTR) extracted from an patient with FAP having variant TTR (Val30Met) would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP. The ATTR fibrils were isolated according to Pras and colleagues as water suspension fractions from an autopsied heart of a Japanese patient with FAP heterozygous with normal and Va130Met variant TTRs. The isolated amyloid fibrils were injected into the tail veins of 8-13-mounth-old transgenic mice. An equal volume of DW was injected into transgenic mice of the same age as controls. After 4 or 12 months, the transgenic mice were killed following anesthetization with ether. Various tissues were excised and subjected to pathological examinations. Twelve months after injection, congophilic amyloid deposits were observed in the various tissues (esophagus, stomach, intestine, lung, liver, kidney, heart) of all the 5 transgenic mice injected with TTR, whereas no deposits were detected in any of the five control transgenic littermates injected with DW. This results clearly showed that ATTR fibrils extracted from the heart of an FAP patient exerted amyloidosis-accelerating activity in vivo. In immunohistochemical analyses, the amyloid deposits in all the five ATTR-injected transgenic mice reacted only with anti-mouse AApoAII antibody, not with anti-human TTR antibody. These results indicated that administration of human ATTR fibrils did accelerate deposition of mouse AApoAII amyloid, and not the same human ATTR. Less