A new role for laminins as modulators of protein toxicity in Caenorhabditis elegans
A new role for laminins as modulators of protein toxicity in Caenorhabditis elegans
复制标题
DOI：
10.1111/j.1474-9726.2011.00767.x
复制
发表时间：
2012-02-01
期刊：
影响因子：
7.8
通讯作者：
Olsen, Anders
中科院分区：
文献类型：
--
作者：
Jensen, Louise T.;Moller, Tine H.;Olsen, Anders
蛋白质错误折叠是衰老和几种与年龄相关的疾病（如阿尔茨海默病和帕金森病）的共同主题。这些疾病的发展过程涉及许多复杂的过程。在这里，我们表明，基底膜（BM）的组成部分，特别是层粘连蛋白，影响蛋白质的完整性，他们支持的肌肉细胞。我们敲低了epi-1（一种层粘连蛋白a链）的基因表达，发现这导致不同秀丽隐杆线虫转基因模型中蛋白毒性增加，在体壁肌肉中表达聚集蛋白。这种效果可以通过减少胰岛素样信号来部分挽救，已知胰岛素样信号可以减缓衰老过程和各种年龄相关疾病的发作。我们的数据指出了一个潜在的分子机制，涉及蛋白酶体降解和HSP-16伴侣活性。此外，epi-1耗竭的动物突触功能改变，并显示出对左旋咪唑和涕灭威（分别为乙酰胆碱受体激动剂和乙酰胆碱酯酶抑制剂）的超敏反应。我们的研究结果暗示BM作为邻近肌细胞中蛋白质稳态的细胞外调节剂。这与先前的研究一致，即神经肌肉信号的不平衡会干扰突触后细胞中蛋白质的稳态。在我们的研究中，蛋白毒性可能确实是由神经肌肉接头介导的，神经肌肉接头是BM的一部分，其中层粘连蛋白以高浓度存在，确保了神经肌肉信号传导的适当微环境。层粘连蛋白在进化上是保守的，因此BM可能在蛋白质错误折叠疾病中发挥比目前认识到的更多的因果作用。
Protein misfolding is a common theme in aging and several age-related diseases such as Alzheimers and Parkinsons disease. The processes involved in the development of these diseases are many and complex. Here, we show that components of the basement membrane (BM), particularly laminin, affect protein integrity of the muscle cells they support. We knocked down gene expression of epi-1, a laminin a-chain, and found that this resulted in increased proteotoxicity in different Caenorhabditis elegans transgenic models, expressing aggregating proteins in the body wall muscle. The effect could partially be rescued by decreased insulin-like signaling, known to slow the aging process and the onset of various age-related diseases. Our data points to an underlying molecular mechanism involving proteasomal degradation and HSP-16 chaperone activity. Furthermore, epi-1-depleted animals had altered synaptic function and displayed hypersensitivity to both levamisole and aldicarb, an acetylcholine receptor agonist and an acetylcholinesterase inhibitor, respectively. Our results implicate the BM as an extracellular modulator of protein homeostasis in the adjacent muscle cells. This is in agreement with previous research showing that imbalance in neuromuscular signaling disturbs protein homeostasis in the postsynaptic cell. In our study, proteotoxicity may indeed be mediated by the neuromuscular junction which is part of the BM, where laminins are present in high concentration, ensuring the proper microenvironment for neuromuscular signaling. Laminins are evolutionarily conserved, and thus the BM may play a much more causal role in protein misfolding diseases than currently recognized.