Garyali Punitee, Siwach Pratibha, Singh Pankaj Kumar, Puri Rajat, Mittal Shuchi, Sengupta Sonali, Parihar Rashmi, Ganesh Subramaniam
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Hum Mol Genet. 2009 Feb 15;18(4):688-700. doi: 10.1093/hmg/ddn398. Epub 2008 Nov 25.
Lafora disease (LD), a progressive form of inherited epilepsy, is associated with widespread neurodegeneration and the formation of polyglucosan bodies in the neurons. Laforin, a protein phosphatase, and malin, an E3 ubiquitin ligase, are two of the proteins that are defective in LD. We have shown recently that laforin and malin (referred together as LD proteins) are recruited to aggresome upon proteasomal blockade, possibly to clear misfolded proteins through the ubiquitin-proteasome system (UPS). Here we test this possibility using a variety of cytotoxic misfolded proteins, including the expanded polyglutamine protein, as potential substrates. Laforin and malin, together with Hsp70 as a functional complex, suppress the cellular toxicity of misfolded proteins, and all the three members of this complex are required for this function. Laforin and malin interact with misfolded proteins and promote their degradation through the UPS. LD proteins are recruited to the polyglutamine aggregates and reduce the frequency of aggregate-positive cells. Taken together, our results suggest that the malin-laforin complex is a novel player in the neuronal response to misfolded proteins and could be potential therapeutic targets for neurodegenerative disorders associated with cytotoxic proteins.
拉福拉病（LD）是一种遗传性癫痫的进行性形式，与广泛的神经退行性变以及神经元中多聚葡萄糖体的形成有关。拉福林是一种蛋白磷酸酶，而马啉是一种E3泛素连接酶，它们是在LD中存在缺陷的两种蛋白质。我们最近发现，拉福林和马啉（统称为LD蛋白）在蛋白酶体阻断时被募集到聚集体中，可能是通过泛素-蛋白酶体系统（UPS）清除错误折叠的蛋白质。在这里，我们使用多种细胞毒性错误折叠蛋白，包括扩展的多聚谷氨酰胺蛋白，作为潜在底物来测试这种可能性。拉福林、马啉与作为功能复合物的热休克蛋白70（Hsp70）一起，抑制错误折叠蛋白的细胞毒性，并且该复合物的所有三个成员对于此功能都是必需的。拉福林和马啉与错误折叠蛋白相互作用，并通过UPS促进其降解。LD蛋白被募集到多聚谷氨酰胺聚集体中，并降低聚集体阳性细胞的频率。综上所述，我们的结果表明，马啉-拉福林复合物是神经元对错误折叠蛋白反应中的一个新参与者，并且可能是与细胞毒性蛋白相关的神经退行性疾病的潜在治疗靶点。
