Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration
Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration
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DOI：
10.1038/nature01832
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发表时间：
2003-07-31
期刊：
影响因子：
64.8
通讯作者：
Lu, KP
中科院分区：
文献类型：
--
作者：
Liou, YC;Sun, A;Lu, KP
阿尔茨海默病和其他tau蛋白病的神经病理学标志包括老年斑和/或神经纤维缠结（1-4）。尽管已经通过过表达特定蛋白质（包括β-淀粉样前体蛋白、早老素和tau（1-10））创建了小鼠模型，但是还没有通过基因敲除产生模型。tau和其他蛋白质在脯氨酸之前的丝氨酸或苏氨酸残基上的磷酸化似乎先于阿尔茨海默病中的缠结形成和神经变性（11-14）。值得注意的是，这些磷酸（Ser/Thr）-Pro基序以两种不同的构象存在，其在某些蛋白质中的转化由Pin 1脯氨酰异构酶催化（15-17）。Pin 1活性可以直接恢复磷酸化tau的构象和功能，也可以通过促进其去磷酸化来间接恢复，这表明Pin 1参与神经变性（14，18，19）;然而，缺乏遗传证据。在这里，我们发现Pin 1的表达与阿尔茨海默病中预测的神经元脆弱性和实际的神经元变性呈负相关。Pin 1基因敲除小鼠可导致进行性年龄依赖性神经病，其特征为运动和行为缺陷、tau蛋白过度磷酸化、tau蛋白丝形成和神经元变性。因此，Pin 1在防止年龄依赖性神经退行性变方面至关重要，为阿尔茨海默病和其他tau蛋白病的发病机制和治疗提供了见解。
The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles(1-4). Although mouse models have been created by overexpressing specific proteins including beta-amyloid precursor protein, presenilin and tau(1-10), no model has been generated by gene knockout. Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer's disease(11-14). Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase(15-17). Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration(14,18,19); however, genetic evidence is lacking. Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioural deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.