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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism
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Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

机译：与家族性阿尔茨海默氏病相关的早老素突变导致磷脂酰肌醇4,5-双磷酸酯代谢失衡

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摘要

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)associated presenilin mutations cause an imbalance in PIP2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg2+-inhibited cation (IMC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP2 closely correlates with 42-residue amyloid beta-peptide (A beta 42) levels. our data suggest that PIP2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A beta 42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP2 may offer a therapeutic approach in Alzheimer's disease.
机译：磷脂酰肌醇4,5-二磷酸（PIP2）是一种重要的细胞效应子，其功能包括调节离子通道和膜运输。 PIP2代谢异常也与多种人类疾病（例如癌症和糖尿病）有关。在这里我们报告家族性早老蛋白突变与家族性阿尔茨海默氏病（FAD）引起PIP2代谢失衡。我们发现瞬态受体电位褪黑素7（TRPM7）相关的Mg2 +抑制阳离子（IMC）通道是早老素FAD突变细胞中离子通道功能障碍的基础，并且观察到的通道缺陷通过添加PIP2（已知的PIP2调节剂）得以恢复。 MIC / TRPM7通道。脂质分析表明，在FAD突变的早老素细胞中PIP2的更新受到选择性影响。我们还发现，细胞PIP2的调节与42个残基的淀粉样蛋白β肽（A beta 42）水平密切相关。我们的数据表明，PIP2失衡可能通过影响多种细胞途径（如毒性A beta 42的产生以及MIC / TRPM7通道的活性，可能与其他神经退行性疾病有关）而促进了阿尔茨海默氏病的发病。因此，我们的研究表明，脑特异性PIP2的调节可能为阿尔茨海默氏病提供一种治疗方法。

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