Mutation in the tau gene in familial multiple system tauopathy with presenile dementia
Mutation in the tau gene in familial multiple system tauopathy with presenile dementia
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DOI：
10.1073/pnas.95.13.7737
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发表时间：
1998-06-23
影响因子：
11.1
通讯作者：
Ghetti, B
中科院分区：
文献类型：
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作者：
Spillantini, MG;Murrell, JR;Ghetti, B
家族性多系统tau蛋白病伴早老性痴呆（Familial Multiple System Tauopathy with Presenile Dementia，MSTD）是一种神经退行性疾病，属于家族性额颞叶痴呆伴17号染色体连锁帕金森综合征（Familial Frontotemporal Dementias with Parkinsonism linked to chromosome 17，FTDP-17），是遗传性痴呆的主要类型，其遗传基础尚不清楚，我们现在报告一个G到A的转换在内含子外显子10的基因微管相关蛋白tau在家族性MSTD。该突变位于GT剪接供体位点的3'相邻核苷酸处，并破坏了预测的茎环结构。我们还报告了一个异常的优势，可溶性tau蛋白亚型与四个微管结合重复的亚型与三个重复在家族性MSTD。这很可能解释了我们先前的发现，即从家族性MSTD的丝状沉积物中提取的肌氨酰不溶性tau蛋白仅由具有四个重复的tau同种型组成。这些发现表明，偏离四重复与三重复tau亚型的正常比例会导致异常tau丝的形成。结果表明，tau蛋白产生的失调可导致神经退行性变，并暗示FTDP-17基因是tau基因。这项工作对阿尔茨海默病和其他tau蛋白病有重要意义。
Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology, It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown, We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.