Crowther R A, Goedert M
Laboratory of Molecular Biology, Medical Research Council, Hills Road, Cambridge, CB2 2QH, United Kingdom.
J Struct Biol. 2000 Jun;130(2-3):271-9. doi: 10.1006/jsbi.2000.4270.
It has been known for some time that the neurofibrillary pathology in Alzheimer's disease consists of so-called paired helical and straight filaments made up of the microtubule-associated protein tau. The degree of dementia observed in the disease correlates better with the extent of neurofibrillary pathology than with the Abeta amyloid deposits, the other characteristic defining pathological fibrous deposit in Alzheimer's disease. However, no familial cases of Alzheimer's disease have been genetically linked to the tau protein locus. Recently a group of frontotemporal dementias with parkinsonism linked to chromosome 17 has been shown to be caused by mutations in the tau gene. Some are missense mutations giving altered tau proteins, whereas others affect the splicing of the pre-mRNA and change the balance between different tau isoforms. Histologically these diseases are all characterised by various kinds of filamentous tau protein deposits, mostly in the complete absence of Abeta deposits. The abnormal tau filaments show different morphologies, depending on the nature of the tau mutation. These diseases show that tau mutations can be a prime cause of inherited dementing illness and may throw some light on the pathological process in the much larger number of sporadic cases of Alzheimer's disease.
一段时间以来，人们已经知道阿尔茨海默病中的神经原纤维病理由所谓的成对螺旋丝和直丝组成，这些丝由微管相关蛋白tau构成。在该疾病中观察到的痴呆程度与神经原纤维病理的程度相关性更好，而不是与β淀粉样蛋白沉积相关，β淀粉样蛋白沉积是阿尔茨海默病中另一个定义病理性纤维沉积的特征。然而，尚未发现阿尔茨海默病的家族病例与tau蛋白基因座存在遗传联系。最近，一组与17号染色体相关的额颞叶痴呆伴帕金森综合征已被证明是由tau基因突变引起的。一些是错义突变，导致tau蛋白发生改变，而另一些则影响前体mRNA的剪接，并改变不同tau异构体之间的平衡。从组织学上看，这些疾病的特征都是各种丝状tau蛋白沉积，大多数情况下完全没有β淀粉样蛋白沉积。异常的tau丝表现出不同的形态，这取决于tau突变的性质。这些疾病表明，tau突变可能是遗传性痴呆疾病的主要原因，并且可能为大量散发性阿尔茨海默病病例的病理过程提供一些线索。
