Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, 342011, India.
Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India.
Mol Neurobiol. 2018 Feb;55(2):1169-1182. doi: 10.1007/s12035-016-0377-2. Epub 2017 Jan 19.
Accumulation of misfolded or aberrant proteins in neuronal cells is linked with neurodegeneration and other pathologies. Which molecular mechanisms fail and cause inappropriate folding of proteins and what is their relationship to cellular toxicity is not well known. How does it happen and what are the probable therapeutic or molecular approaches to counter them are also not clear. Here, we demonstrate that treatment of lanosterol diminishes aberrant proteotoxic aggregation and mitigates their cytotoxicity via induced expression of co-chaperone CHIP and elevated autophagy. The addition of lanosterol not only reduces aggregation of mutant bonafide misfolded proteins but also effectively prevents accumulation of various mutant disease-prone proteotoxic proteins. Finally, we observed that lanosterol mitigates cytotoxicity in cells, mediated by different stress-inducing agents. Taken together, our present results suggest that upregulation of cellular molecular chaperones, primarily using small molecules, can probably offer an efficient therapeutic approach in the future against misfolding of different disease-causing proteins and neurodegenerative disorders. Graphical Abstract ᅟ.
神经元细胞中错误折叠或异常蛋白质的积累与神经退行性变和其他病理学有关。哪些分子机制失效导致蛋白质的异常折叠，以及它们与细胞毒性的关系尚不清楚。它是如何发生的，以及可能的治疗或分子方法来对抗它们也不清楚。在这里，我们证明了羊毛甾醇的治疗可以通过诱导共伴侣 CHIP 的表达和提高自噬来减少异常蛋白毒性聚集，并减轻其细胞毒性。羊毛甾醇的添加不仅减少了突变的良性错误折叠蛋白的聚集，而且还有效地防止了各种突变的疾病相关蛋白毒性蛋白的积累。最后，我们观察到羊毛甾醇可以减轻不同应激诱导剂介导的细胞毒性。总之，我们目前的结果表明，上调细胞分子伴侣，主要使用小分子，可能为未来对抗不同致病蛋白的错误折叠和神经退行性疾病提供有效的治疗方法。
