Pickering-Brown S M, Baker M, Nonaka T, Ikeda K, Sharma S, Mackenzie J, Simpson S A, Moore J W, Snowden J S, de Silva R, Revesz T, Hasegawa M, Hutton M, Mann D M A
Greater Manchester Neurosciences Centre, Humphrey Booth Building, Hope Hospital, Stott Lane, Salford M6 8HD, UK.
Brain. 2004 Jun;127(Pt 6):1415-26. doi: 10.1093/brain/awh147. Epub 2004 Mar 26.
In this report, we describe the clinical and neuropathological features of a case of familial frontotemporal dementia (FTD), with onset at 58 years of age and disease duration of 10 years, associated with a novel mutation, Q336R, in the tau gene (tau). In vitro studies concerning the properties of tau proteins bearing this mutation, with respect to microtubule assembly and tau filament aggregation, are reported. Clinically, the patient showed alterations in memory, language and executive functions and marked behavioural change consistent with FTD, although the extent of memory impairment was more than is characteristic of FTD. At autopsy, there was degeneration of the frontal and temporal lobes associated with the presence of hyperphosphorylated tau proteins in swollen (Pick) cells and intraneuronal inclusions (Pick bodies). By immunohistochemistry, the Pick bodies contained both 3-repeat and 4-repeat tau proteins although, because no fresh tissues were available for analysis, the exact isoform composition of the aggregated tau proteins could not be determined. Neurons within frontal cortex contained neurofibrillary tangle-like structures, comprising both straight and twisted tubules, or Pick bodies in which the filaments were short and randomly orientated. In vitro, and in common with other tau missense mutations, Q336R caused an increase in tau fibrillogenesis. However, in contrast to most other tau missense mutations, Q336R increased, not decreased, the ability of mutant tau to promote microtubule assembly. Nonetheless, this latter functional change may likewise be detrimental to neuronal function by inducing a compensatory phosphorylation that may yield increased intracellular hyperphosphorylated tau species that are also liable to fibrillize. We believe the mutation is indeed pathogenic and disease causing and not simply a coincidental rare and benign polymorphism. Since this mutation is segregating with the FTD clinical and neuropathological phenotype, it has not been found in unaffected individuals and it has novel functional properties in vitro which are likely to be detrimental to neuronal function in vivo.
在本报告中，我们描述了一例家族性额颞叶痴呆（FTD）患者的临床和神经病理学特征。该患者58岁起病，病程10年，与tau基因（tau）中的一种新突变Q336R相关。本文报告了关于携带此突变的tau蛋白在微管组装和tau丝聚集方面特性的体外研究。临床上，患者表现出记忆、语言和执行功能改变以及与FTD一致的明显行为变化，尽管记忆障碍程度超过了FTD的特征表现。尸检时，额叶和颞叶出现变性，伴有肿胀（Pick）细胞和神经元内包涵体（Pick小体）中存在过度磷酸化的tau蛋白。通过免疫组织化学方法，Pick小体中同时含有3重复和4重复的tau蛋白，不过由于没有新鲜组织用于分析，无法确定聚集的tau蛋白的确切异构体组成。额叶皮质内的神经元含有神经原纤维缠结样结构，包括直的和扭曲的微管，或其中细丝短且随机排列的Pick小体。在体外，与其他tau错义突变一样，Q336R导致tau纤维形成增加。然而，与大多数其他tau错义突变不同的是，Q336R增加而非降低了突变tau促进微管组装的能力。尽管如此，后一种功能变化同样可能通过诱导代偿性磷酸化对神经元功能有害，这种磷酸化可能产生更多细胞内过度磷酸化的tau物种，这些物种也易于纤维化。我们认为该突变确实具有致病性并可导致疾病，而不仅仅是一种偶然的罕见良性多态性。由于这种突变与FTD的临床和神经病理学表型共分离，未在未受影响的个体中发现，且在体外具有新的功能特性，这些特性可能在体内对神经元功能有害。
