Many diseases are caused by aberrant accumulation of certain proteins that are misfolded and cytotoxic, and lowering the level of these proteins provides promising treatment strategies for these diseases. We hypothesized that compounds that interact with both the disease-causing protein and the phagophore (autophagosome precursor) protein LC3 may tether the former to phagophores for subsequent autophagic degradation. If true, this autophagosome-tethering compound (ATTEC) concept could be applied to many disease-causing proteins to treat diseases. We tested this hypothesis in the scenario of Huntington disease (HD), a neurodegenerative disorder that is caused by the mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) stretch. In our recent study, we designed a small-molecule microarray-based screening and identified four mHTT-lowering compounds that interact with both mHTT and LC3, but not wild-type (WT) HTT. These compounds target mHTT to phagophores for autophagic degradation without influencing the WT HTT level, and rescue HD-relevant phenotypes in HD cells and in vivo in the fly and mouse HD models. Interestingly, these compounds interact with the expanded polyQ stretch directly and are able to reduce other disease-causing proteins with expanded polyQ. In summary, our study provides the initial validation of lowering mHTT by ATTEC, providing entry points to new treatment strategies of HD and similar diseases.

中文翻译：

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ATTEC：靶向蛋白病的潜在新方法。

许多疾病是由错误折叠并具有细胞毒性的某些蛋白质的异常积累引起的，降低这些蛋白质的水平可为这些疾病提供有希望的治疗策略。我们假设与致病蛋白和吞噬体（自噬体前体）蛋白LC3相互作用的化合物可能将前者束缚在吞噬体上，以进行随后的自噬降解。如果为真，这种自噬连接蛋白（ATTEC）的概念可以应用于许多引起疾病的蛋白质来治疗疾病。我们在亨廷顿病（HD）的情况下测试了该假设，亨廷顿病（HD）是由变性HTT（mHTT）蛋白和扩展的聚谷氨酰胺（polyQ）延伸引起的神经退行性疾病。在我们最近的研究中 我们设计了一种基于小分子微阵列的筛选方法，并鉴定了四种与mHTT和LC3相互作用但与野生型（WT）HTT不相互作用的降低mHTT的化合物。这些化合物将mHTT靶向于自噬降解的吞噬细胞，而不会影响WT HTT水平，并在飞行和小鼠HD模型中挽救HD细胞和体内HD相关的表型。有趣的是，这些化合物直接与扩展的polyQ相互作用，并能够通过扩展的polyQ减少其他致病蛋白。总而言之，我们的研究提供了ATTEC降低mHTT的初步验证，为HD和类似疾病的新治疗策略提供了切入点。这些化合物将mHTT靶向于自噬降解的吞噬细胞，而不会影响WT HTT水平，并在飞行和小鼠HD模型中挽救了HD细胞和体内HD相关的表型。有趣的是，这些化合物直接与扩展的polyQ相互作用，并能够通过扩展的polyQ减少其他致病蛋白。总而言之，我们的研究提供了ATTEC降低mHTT的初步验证，为HD和类似疾病的新治疗策略提供了切入点。这些化合物将mHTT靶向于自噬降解的吞噬细胞，而不会影响WT HTT水平，并在飞行和小鼠HD模型中挽救HD细胞和体内HD相关的表型。有趣的是，这些化合物与扩展的polyQ片段直接相互作用，并能够通过扩展的polyQ减少其他致病蛋白。总而言之，我们的研究提供了ATTEC降低mHTT的初步验证，为HD和类似疾病的新治疗策略提供了切入点。