Garruto Ralph M
Laboratory of Central Nervous System Studies, National Institutes of Health, Bethesda, Maryland 20892.
Am J Hum Biol. 1989;1(5):529-543. doi: 10.1002/ajhb.1310010504.
Hyperendemic Pacific foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) represent naturally occurring models of late-onset chronic degenerative diseases that occur in different cultures, in different ecological zones, and among genetically divergent populations. These diseases occur among the Chamorros of the Mariana Islands, among the Auyu and Jakai of southern West New Guinea, and among the Japanese from the Kill Peninsula of Honshu Island. Accumulating evidence supports the hypothesis that a defect in mineral metabolism may be etiologically involved. Toxic and essential elements, such as calcium aluminum, and silicon cross the blood-brain barrier, deposit in affected neurons, and disrupt the axonal transport system, resulting in the abnormal copolymerization of cytoskeletal and amyloid β-proteins in neurons. The pathological accumulation of these and other proteins into neurofibrillary tangles (the hallmark neuropathological lesion) causes neuronal dysfunction and death. Recent immunocytochemical and biochemical studies indicate that the amyloid β-protein in Guamanian PD has an identical amino acid sequence, a similar N-terminus heterogeneity (variation in polypeptide length), and a similar immunoreactivity to those found in Alzheimer disease, suggesting a common mechanism of pathogenesis. Investigations are now underway to determine whether the abnormal accumulation of amyloid β-protein in neurons of Guamanian patients with ALS and PD is the result of an aberrant post-translational modification of a larger precursor protein, an additional copy of the amyloid gene, or an impairment of amyloid catabolism all of which may be mediated by metal-enzyme or metal-gene interactions. The abnormal copolymerization of other proteins such as neurofilament, microtubule-associated protein tau, and ubiquitin in affected neurons suggests their interrelationship in the disease process.
肌萎缩侧索硬化症（ALS）和帕金森痴呆症（PD）的高度流行的太平洋病灶代表了迟发性慢性退行性疾病的自然发生模型，这些疾病发生在不同文化、不同生态区域以及基因不同的人群中。这些疾病出现在马里亚纳群岛的查莫罗人、新几内亚岛西部南部的奥尤人和贾凯人以及本州岛基尔半岛的日本人当中。越来越多的证据支持这样一种假说，即矿物质代谢缺陷可能在病因上与之相关。有毒和必需元素，如钙、铝和硅，穿过血脑屏障，沉积在受影响的神经元中，并破坏轴突运输系统，导致神经元中细胞骨架蛋白和淀粉样β蛋白异常共聚。这些蛋白质和其他蛋白质病理性积聚形成神经原纤维缠结（标志性的神经病理病变），导致神经元功能障碍和死亡。最近的免疫细胞化学和生化研究表明，关岛帕金森痴呆症中的淀粉样β蛋白具有与阿尔茨海默病中相同的氨基酸序列、相似的N端异质性（多肽长度变化）以及相似的免疫反应性，提示存在共同的发病机制。目前正在进行调查，以确定关岛肌萎缩侧索硬化症和帕金森痴呆症患者神经元中淀粉样β蛋白的异常积聚是否是较大前体蛋白翻译后修饰异常、淀粉样基因的额外拷贝或淀粉样蛋白分解代谢受损的结果，所有这些都可能由金属酶或金属基因相互作用介导。受影响神经元中其他蛋白质，如神经丝、微管相关蛋白tau和泛素的异常共聚表明它们在疾病过程中的相互关系。
