Bronner I F, ter Meulen B C, Azmani A, Severijnen L A, Willemsen R, Kamphorst W, Ravid R, Heutink P, van Swieten J C
Department of Human Genetics, Section Medical Genomics and Center for Neurogenomics and Cognitive Research, VU University Medical Center and VU University, Amsterdam, The Netherlands.
Brain. 2005 Nov;128(Pt 11):2645-53. doi: 10.1093/brain/awh591. Epub 2005 Jul 13.
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 Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.
与17号染色体相关的额颞叶痴呆和帕金森症与微管相关蛋白tau（MAPT或tau）基因的突变有关。这种疾病的特征是在不同脑区存在大量神经元和胶质tau病变。在一个患有G272V突变的遗传性皮克病家族以及几个外显子9和11 - 13存在其他tau突变的家族中发现了皮克小体。这些突变之间皮克小体的生化组成有所不同。直到最近，由于无法获得新鲜冷冻的脑材料，尚未对G272V脑材料进行详细的生化特征分析。我们现在报告一项详细研究，该研究使用免疫组织化学、蛋白质免疫印迹法和电子显微镜对最近可获得的两个具有G272V突变的大脑进行分析。两个大脑均显示颞叶皮质严重神经元丢失，而额叶皮质的丢失较少；海马齿状回和尾状核中有大量皮克小体。皮克小体仅由三重复（3R）异构体组成，这通过异构体特异性抗体得以证明，并得到了 Sarkosyl不溶性tau的蛋白质免疫印迹分析的支持。这些观察结果证实，这个被诊断为遗传性皮克病的家族符合这种疾病的所有标准，包括存在在Ser262处未磷酸化且包含仅由3R tau组成的长周期扭曲细丝的皮克小体。
