Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease
Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease
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DOI：
10.1002/ana.21192
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发表时间：
2007-08-01
影响因子：
11.2
通讯作者：
Sawcer, Stephen J.
中科院分区：
文献类型：
--
作者：
Goris, An;Williams-Gray, Caroline H.;Sawcer, Stephen J.
目的：帕金森病（PD）是一种神经退行性疾病，通常表现为运动障碍，但已知与不同程度的认知障碍（包括痴呆）相关。我们调查了这种疾病的易感性和认知异质性的遗传基础。方法：在659例PD患者中，其中109例从诊断开始随访了3.5年，2,176例对照组，我们研究了参与蛋白质聚集和包涵体形成的候选基因，这是帕金森综合征的病理标志：微管相关蛋白tau（MAPT）、糖原合成酶激酶-3 β（GSK 3B）和（x-突触核蛋白（SNCA））。我们观察到认知功能下降和PD痴呆的发展密切相关（p = 10（-4））我们还发现MAPT倒位多态性与SNCA 3'区单核苷酸多态性rs356219之间存在一种新的协同作用。在我们的数据中，在这两个基因座中的任何一个上携带风险基因型都会略微增加患PD的风险，而在这两个基因座上携带风险基因型的组合则会使患PD的风险增加约一倍（p = 3x10（-6））。我们的数据支持tau蛋白和α-突触核蛋白参与PD发病机制中的共享或会聚途径的假设，提示tau蛋白倒位影响特发性PD患者认知功能障碍和痴呆的发展。这些发现对于理解神经退行性疾病中tau和α-突触核蛋白通路之间的界面以及解开PD中认知障碍和痴呆的生物学基础具有潜在的重要意义。
Objective: Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease.Methods: In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of Parkinsonism: microtubule-associated protein tau (MAPT), glycogen synthase kinase-3 beta (GSK3B), and (x-synuclein (SNCA).Results: We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10(-4)) with the inversion polymorphism containing MAPT We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3' region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 x 10(-6)).Interpretation: Our data support the hypothesis that tau and alpha-synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and alpha-synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD.