PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4.
PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4.
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DOI：
10.1016/j.celrep.2020.108224
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发表时间：
2020-10-06
期刊：
影响因子：
8.8
通讯作者：
Lindquist S
中科院分区：
文献类型：
--
作者：
Narayan P;Sienski G;Bonner JM;Lin YT;Seo J;Baru V;Haque A;Milo B;Akay LA;Graziosi A;Freyzon Y;Landgraf D;Hesse WR;Valastyan J;Barrasa MI;Tsai LH;Lindquist S
载脂蛋白 E (APOE4) 的 e4 等位基因是许多疾病的遗传风险因素，包括迟发性阿尔茨海默病 (AD)。我们研究了 APOE4 在人 iPSC 衍生的星形胶质细胞中的细胞影响。与同基因 APOE3 星形胶质细胞相比，我们观察到 APOE4 星形胶质细胞存在内吞缺陷。鉴于内吞作用在进化上的保守性，我们建立了一个酵母模型来识别与 APOE4 相关的内吞缺陷的遗传修饰剂。在酵母中，只有 APOE4 的表达在内吞作用和生长方面表现出剂量依赖性缺陷。我们发现，早期内吞衔接蛋白 Yap1802p（人类 AD 危险因子 PICALM 的同源物）表达的增加可以挽救 APOE4 诱导的内吞缺陷。在 iPSC 衍生的人星形胶质细胞中，增加 PICALM 的表达同样可以逆转内吞破坏。我们的工作确定了两种 AD 遗传风险因素（APOE4 和 PICALM）之间的功能相互作用，其重点是保守的内吞作用生物学过程。
The e4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases including late onset Alzheimer’s Disease (AD). We investigated the cellular consequences of APOE4 in human iPSC-derived astrocytes. We observed an endocytic defect in APOE4 astrocytes compared to their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only expression of APOE4 exhibits dose-dependent defects in both endocytosis and growth. We discovered that increasing expression of the early endocytic adaptor protein, Yap1802p, homolog of the human AD risk factor PICALM, rescued the APOE4-induced endocytic defect. In iPSC-derived human astrocytes increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors—APOE4 and PICALM—centered on the conserved biological process of endocytosis.
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