Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology
Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology
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DOI：
10.1093/brain/awh591
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发表时间：
2005-11-01
期刊：
影响因子：
14.5
通讯作者：
van Swieten, JC
中科院分区：
文献类型：
--
作者：
Bronner, IF;ter Meulen, BC;van Swieten, JC
与17号染色体相关的额颞痴呆和帕金森病与微管相关蛋白tau(MAPT或tau)基因的突变有关。这种疾病的特点是在不同的脑区有大量的神经元和神经胶质tau损伤。在一个带有G272V突变的遗传性Pick病家系中发现了Pick小体，在几个外显子9和11-13中有其他tau突变的家系中发现了Pick小体。在这些突变之间，Pick小体的生化组成各不相同。直到最近，由于没有新鲜的冷冻脑组织材料，还没有对G272V脑组织材料进行详细的生化表征。我们现在报告一项详细的研究，使用免疫组织化学、蛋白质印迹和电子显微镜对两个最近出现的G272V突变的大脑进行研究。两脑均表现为颞叶皮质神经元严重丢失，而额叶皮质神经元丢失较少；在海马齿状回和尾状核有丰富的Pick小体。Pick小体完全由三个重复(3R)亚型组成，异构体特异性抗体证实了这一点，并得到了不溶于肌糖的tau的蛋白质印迹分析的支持。这些观察证实，这个被诊断为遗传性Pick病的家系符合该疾病的所有标准，包括存在Ser(262)处未磷酸化的Pick小体，并含有仅由3R tau组成的长周期扭曲的细丝。
Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser(262) and contain twisted filaments with long periodicity consisting only of 3R tau.