The role of tau in the pathological process and clinical expression of Huntington's disease.
The role of tau in the pathological process and clinical expression of Huntington's disease.
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DOI：
10.1093/brain/awv107
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Barker RA
中科院分区：
文献类型：
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作者：
Vuono R;Winder-Rhodes S;de Silva R;Cisbani G;Drouin-Ouellet J;REGISTRY Investigators of the European Huntington’s Disease Network;Spillantini MG;Cicchetti F;Barker RA
Tau蛋白最近被认为与亨廷顿氏病有关，但其参与的性质尚不清楚。Vuono等人揭示了死后亨廷顿病大脑中的tau低聚物和过度磷酸化的tau聚集体，包括那些年轻发病的病例。一项大型患者队列的基因型-表型分析显示，tau单倍型影响认知能力下降。Tau蛋白最近被认为与亨廷顿氏病有关，但其参与的性质尚不清楚。Vuono等人揭示了死后亨廷顿病大脑中的tau低聚物和过度磷酸化的tau聚集体，包括那些年轻发病的病例。一项大型患者队列的基因型-表型分析显示，tau单倍型影响认知能力下降。亨廷顿氏病是一种神经退行性疾病，由亨廷顿蛋白基因HTT外显子1内异常CAG重复扩增引起。虽然几种不同于亨廷顿舞蹈病位点本身的遗传修饰因子已被确定与亨廷顿舞蹈病的临床表达和进展有关，但驱动其致病级联和临床特征（特别是痴呆症）的确切分子机制尚不完全清楚。最近，与几种神经退行性疾病相关的微管相关蛋白tau （MAPT）被认为与亨廷顿氏病有关。我们在神经病理、遗传和临床水平上更详细地探讨了这种联系。我们首先通过在亨廷顿病患者（n = 16）的死后脑样本中寻找过度磷酸化的tau聚集体、tau与突变HTT及其寡聚中间体的共定位来研究tau病理学，并将其与已知的tau病和健康对照进行比较。接下来，我们对一大批亨廷顿舞蹈病患者（n = 960）进行了基因型-表型分析，特别关注认知能力下降。我们不仅报道了亨廷顿病脑中的tau病理，而且还报道了tau基因的遗传变异与疾病的临床表达和进展之间的关系。我们发现广泛的病理包涵体含有异常磷酸化的tau蛋白，在某些情况下与突变的HTT共定位。我们证实这与疾病过程有关，而不是年龄，通过显示它也存在于两名年轻发病的亨廷顿舞蹈病患者（死亡时分别为26岁和40岁）。此外，我们证明tau寡聚物（被认为是最有可能的神经毒性tau实体）存在于亨廷顿氏病的大脑中。最后，我们通过证明MAPT单倍型影响亨廷顿舞蹈病患者的认知能力下降率，强调了这种病理学的临床意义。因此，我们的发现突出了tau蛋白在亨廷顿氏病的致病过程和临床表达中的重要作用，从而为这种无法治愈的疾病开辟了新的治疗途径。
Tau has recently been implicated in Huntington’s disease, but the nature of its involvement is unclear. Vuono et al. reveal tau oligomers and hyperphosphorylated tau aggregates in post-mortem Huntington’s disease brains, including those from young-onset cases. Genotype-phenotype analysis of a large patient cohort shows that tau haplotypes influence cognitive decline. Tau has recently been implicated in Huntington’s disease, but the nature of its involvement is unclear. Vuono et al. reveal tau oligomers and hyperphosphorylated tau aggregates in post-mortem Huntington’s disease brains, including those from young-onset cases. Genotype-phenotype analysis of a large patient cohort shows that tau haplotypes influence cognitive decline. Huntington’s disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington’s disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington’s disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington’s disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington’s disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype–phenotype analysis of a large cohort of patients with Huntington’s disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington’s disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington’s disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington’s disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington’s disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington’s disease, which in turn opens up new therapeutic avenues for this incurable condition.