Modeling endophilin-mediated A beta disposal in glioma cells
Modeling endophilin-mediated A beta disposal in glioma cells
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模拟神经胶质瘤细胞中内亲素介导的 Aβ 处理
DOI：
10.1016/j.bbamcr.2018.06.015
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发表时间：
2018
影响因子：
5.1
通讯作者：
Zhang Yaou
中科院分区：
文献类型：
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作者：
Sun Bing;Fan Ping;Liao Meijian;Zhang Yaou
自噬失调已经出现在与年龄相关的神经系统疾病中（Ulland等人; Matheoud等人; Ashkenazi et al.）。阿尔茨海默病（AD）是最常见的进行性神经变性疾病，其特征在于由异常Aβ代谢引起的淀粉样蛋白-β（Aβ）斑块的积累（Qiang et al.; Sevigny等人; Ittner等人）。胶质细胞构成脑免疫系统，并通过自噬-溶酶体机制摄取细胞外Aβ进行降解（Ries和Sastre; Cho等人）。在这里，我们通过显示miR 34 a抑制自噬介导的Aβ原纤维处置并鉴定miR 34 a的两种新的直接靶点，即内亲和素-3和组织蛋白酶B（CTSB，一种先前报道的Aβ降解酶（Sun et al.）），来模拟神经胶质瘤细胞中这种清除过程的分子原理。生物信息学分析显示，在神经退行性疾病中，endophilin-3的表达水平显著降低。其功能获得显著促进Aβ的摄取和降解，而小干扰RNA（siRNA）介导的内啡肽-3敲低可减缓Aβ清除并阻断自体溶酶体形成。从机制上讲，通过质谱法鉴定的亲内蛋白-3相互作用组的基因本体论（GO）分析揭示了参与肌动蛋白结合的富集组分（得分最高）。重要的是，我们验证了肌动蛋白结合蛋白phostensin相互作用与endophilin-3。Phostensin敲低恢复了内啡肽-3介导的Aβ清除上调。因此，我们的研究结果表明，miR 34 a通过靶向内亲和素-3和CTSB在多个步骤（包括摄取和自噬介导的降解）抑制Aβ清除。
Autophagy dysregulation has emerged in age-related neurological diseases (Ulland et al.; Matheoud et al.; Ashkenazi et al.). Alzheimer Disease (AD), the most common progressive neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) plaques caused by aberrant Aβ metabolism (Qiang et al.; Sevigny et al.; Ittner et al.). Glia constitute the brain immune system and ingest extracellular Aβ for degradation via the autophagy-lysosome machinery (Ries and Sastre; Cho et al.). Here, we model the molecular rationale for this clearance process in glioma cells by showing that miR34a inhibits autophagy-mediated disposal of Aβ fibrils and identifying two novel direct targets of miR34a, endophilin-3 and cathepsin B (CTSB, a previously reported enzyme for Aβ degrading (Sun et al.)). Bioinformatics analyses revealed that endophilin-3 expresses at a significantly lower level in neurodegenerative diseases. Its gain-of-function substantially promotes both uptake and degradation of Aβ while small interfering RNA (siRNA)-mediated endophilin-3 knockdown slowed down Aβ clearance and blocked autolysosome formation. Mechanistically, gene ontology (GO) analysis of the endophilin-3 interactome identified by mass spectrometry uncovered enriched components involved in actin binding (with the highest score). Importantly, we validated that the actin-binding protein phostensin interacted with endophilin-3. Phostensin knockdown restored endophilin-3-mediated up-regulation of Aβ clearance. Thus, our findings indicate that miR34a inhibits Aβ clearance by targeting endophilin-3 and CTSB at multiple steps including uptake and autophagy-mediated degradation.