Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam
Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam
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DOI：
10.1073/pnas.1322614111
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发表时间：
2014-01-21
影响因子：
11.1
通讯作者：
Iqbal, Khalid
中科院分区：
文献类型：
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作者：
Arif, Mohammad;Kazim, Syed Faraz;Iqbal, Khalid
关岛帕金森-痴呆（PD）是一种神经退行性疾病，伴有帕金森病和早发性阿尔茨海默样痴呆，与由过度磷酸化的微管相关蛋白tau组成的神经原纤维缠结相关。β - n -甲基氨基- l -丙氨酸（BMAA）一直被怀疑与PD的病因有关，但BMAA导致tau过度磷酸化的机制尚不清楚。我们发现，在关岛PD患者的大脑中，蛋白磷酸酶2A （PP2A）活性的降低与其催化亚基PP2Ac在Tyr（307）的抑制性磷酸化的增加和tau的异常过度磷酸化有关。为了验证BMAA可能参与PD的发病机制，我们研究了这种环境神经毒素对小鼠原代神经元培养物和代谢活跃的大鼠脑切片中PP2A活性和tau过度磷酸化的影响。BMAA处理显著降低PP2A活性，同时增加tau激酶活性，导致PP2A有利位点的tau过度磷酸化升高。此外，我们发现在bmaa处理的大鼠脑中，PP2Ac在Tyr（307）的磷酸化增加。代谢性谷氨酸受体5 （mGluR5）和Src拮抗剂预处理可阻断bmaa诱导的PP2A抑制和tau异常过度磷酸化，表明参与了Src依赖性的PP2A通路。共免疫沉淀实验表明，BMAA处理将PP2Ac从mGluR5中解离，使其可在Tyr位点磷酸化（307）。这些发现表明，BMAA可以通过mGluR5的激活抑制PP2A，从而导致mGluR5-PP2A复合物中PP2Ac的释放，以及Src在Tyr（307）上的磷酸化，从而导致tau病理。
Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. beta-N-methylamino-L-alanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr(307) and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr(307) in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAA-induced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr(307). These findings suggest a scenario inwhich BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr(307) by Src.