Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C-elegans
Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C-elegans
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DOI：
10.4161/auto.4776
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发表时间：
2007-11-01
期刊：
影响因子：
13.3
通讯作者：
Link, Christopher D.
中科院分区：
文献类型：
--
作者：
Florez-McClure, Maria L.;Hohsfield, Lindsay A.;Link, Christopher D.
自噬是一种保守的膜运输途径，介导细胞质底物递送到溶酶体进行降解。自噬功能受损与各种神经退行性疾病的病理学有关。我们已经产生了转基因C。表达人类（β-淀粉样肽（A β），以检查A β毒性的机制）的线虫。在该模型中，A β表达导致自噬体积累，从而模拟阿尔茨海默病患者大脑中发现的病理学。此外，我们证明，减少胰岛素受体信号[使用daf-2（e 1370）突变]抑制A β诱导的瘫痪的机制，需要自噬。令人惊讶的是，daf-2突变也减少了A β诱导的自噬体积累。这些观察结果可以通过一个模型来解释，在该模型中，胰岛素受体信号传导减少促进自噬体成熟为降解性自溶酶体，而A β削弱了这一过程。与该模型一致，我们发现RNAi介导的溶酶体组分敲低导致增强的A β毒性和自噬体积累。此外，A β; daf-2（e 1370）线虫比A β或对照菌株含有更多的溶酶体。最后，我们证明了胰岛素受体信号的减少促进了A β的自噬降解。
Autophagy is a conserved membrane trafficking pathway that mediates the delivery of cytoplasmic substrates to the lysosome for degradation. Impaired autophagic function is implicated in the pathology of various neurodegenerative diseases. We have generated transgenic C. elegans that express human (beta-amyloid peptide (A beta) in order to examine the mechanisms) of A beta-toxicity. In this model, A beta expression causes autophagosome accumulation, thereby mimicking a pathology found in brains of Alzheimer's disease patients. Furthermore, we demonstrate that decreased insulin-receptor signaling [using the daf-2(e 1370) mutation] suppresses A beta-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases A beta-induced autophagosome accumulation. These observations can be explained by a model in which decreased insulin-receptor signaling promotes the maturation of autophagosomes into degradative autolysosomes, whereas A beta impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced A beta-toxicity and autophagosome accumulation. Also, A beta; daf-2(e 1370) nematodes contain more lysosomes than either A beta or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of A beta.