Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17
Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17
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DOI：
10.1073/pnas.95.22.13103
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发表时间：
1998-10-27
影响因子：
11.1
通讯作者：
Wilhelmsen, KC
中科院分区：
文献类型：
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作者：
Clark, LN;Poorkaj, P;Wilhelmsen, KC
苍白球-脑桥-黑质变性（Pallido-ponto-nigral degeneration，PPND）是与染色体17 q21 -22相关的家族性神经退行性疾病之一，这些遗传性疾病统称为与染色体17相关的额颞叶痴呆（frontotemporal dementia，FTD）和帕金森综合征（parkinsonism linked to chromosome 17，FTDP-17）。FTDP-17脑的诊断性损伤是神经元和神经胶质细胞的特定亚群的细胞质中富含tau的细丝。微管相关蛋白（tau）基因位于染色体17 q21 -22。出于这些原因，我们研究了PPND和其他FTDP-17综合征可能由tau基因突变引起的可能性。在PPND家系中发现了（Asn）279（Lys）错义突变，在其他4个FTDP-17激酶中发现了（Pro）301（Leu）错义突变，在另一个FTDP-17家系中发现了第3个错义突变，位于第10外显子3'剪接位点附近的内含子。含有外显子10的转录物编码具有四个微管（MT）结合重复的tau同种型（4 Rtau），而不是具有三个MT结合重复的tau同种型（3Rtau）。使用tau特异性抗体通过免疫印迹分析从具有每种突变的患者的脑中分离的不溶性tau聚集体。对于三种突变中的每一种，观察到具有64和69的表观M-r的异常tau。去磷酸化的物质与含有具有四个MT结合重复序列的外显子10的tau同种型共迁移，但不与3Rtau共迁移。因此，具有错义突变和剪接点突变的患者的脑在丝状包涵体中含有不溶性4 Rtau的聚集体，这可能导致神经变性。
Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21-22, These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17), Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21-22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, (Asn)279(Lys) in the PPND kindred and (Pro)301(Leu) in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3' splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT) binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau),The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies, For each of three mutations, abnormal tau with an apparent M-r of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau, Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.