Florez-McClure Maria L, Hohsfield Lindsay A, Fonte Gin, Bealor Matthew T, Link Christopher D
Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, USA.
Autophagy. 2007 Nov-Dec;3(6):569-80. doi: 10.4161/auto.4776. Epub 2007 Jul 20.
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 (Abeta) in order to examine the mechanism(s) of Abeta-toxicity. In this model, Abeta 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(e1370) mutation] suppresses Abeta-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases Abeta-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 Abeta impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced Abeta-toxicity and autophagosome accumulation. Also, Abeta; daf-2(e1370) nematodes contain more lysosomes than either Abeta or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of Abeta.
自噬是一种保守的膜运输途径，介导细胞质底物向溶酶体的转运以进行降解。自噬功能受损与多种神经退行性疾病的病理过程有关。我们构建了在秀丽隐杆线虫中表达人β淀粉样肽（Aβ）的转基因线虫，以研究Aβ毒性的机制。在这个模型中，Aβ的表达导致自噬体积累，从而模拟了阿尔茨海默病患者大脑中发现的病理现象。此外，我们证明降低胰岛素受体信号传导[使用daf-2（e1370）突变]通过一种需要自噬的机制抑制Aβ诱导的麻痹。令人惊讶的是，daf-2突变也减少了Aβ诱导的自噬体积累。这些观察结果可以用一个模型来解释，即降低胰岛素受体信号传导促进自噬体成熟为具有降解功能的自溶酶体，而Aβ损害了这个过程。与该模型一致，我们发现RNA干扰介导的溶酶体成分敲低导致Aβ毒性增强和自噬体积累。此外，Aβ；daf-2（e1370）线虫比Aβ或对照品系含有更多的溶酶体。最后，我们证明降低胰岛素受体信号传导促进Aβ的自噬降解。
