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首页> 外文期刊>Nature >Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration
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Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration

机译：脯氨酰异构酶Pin1在预防年龄依赖性神经变性中的作用

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The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles. Although mouse models have been created by over-expressing specific proteins including β-amyloid precursor protein, presenilin and tau, 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. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase. 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; 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.
机译：阿尔茨海默氏病和其他创伤性病变的神经病理学特征包括老年斑和/或神经原纤维缠结。尽管已经通过过表达包括β-淀粉样蛋白前体蛋白，早老素和tau蛋白在内的特定蛋白来创建小鼠模型，但基因敲除还没有产生任何模型。脯氨酸之前的丝氨酸或苏氨酸残基上的tau和其他蛋白的磷酸化似乎早于阿尔茨海默氏病的缠结形成和神经变性。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，它们在某些蛋白质中的转化是由Pin1脯氨酰异构酶催化的。 Pin1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而间接恢复，这表明Pin1参与了神经退行性变。但是，缺乏遗传证据。在这里，我们显示Pin1表达与阿尔茨海默氏病中预测的神经元易损性和实际的神经原纤维变性成反比。小鼠中的Pin1基因敲除会导致进行性年龄依赖性神经病变，其特征是运动和行为缺陷，tau过度磷酸化，tau细丝形成和神经元变性。因此，Pin1在防止年龄依赖性神经退变方面起着至关重要的作用，它为阿尔茨海默氏病和其他疾病的发病机理和治疗提供了见识。

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