Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, China.
Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China.
Autophagy. 2020 Jan;16(1):185-187. doi: 10.1080/15548627.2019.1688556. Epub 2019 Nov 7.
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 uophagosome-thering ompound (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 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.
许多疾病是由异常积累错误折叠和细胞毒性的特定蛋白质引起的，降低这些蛋白质的水平为这些疾病提供了有前途的治疗策略。我们假设，与致病蛋白和噬菌斑（自噬体前体）蛋白 LC3 都相互作用的化合物可能将前者与噬菌斑连接起来，以便随后进行自噬降解。如果这是真的，那么这种 uophagosome-thering ompound（ATTEC）概念可以应用于许多致病蛋白来治疗疾病。我们在亨廷顿病（HD）的情况下测试了这一假设，亨廷顿病是一种神经退行性疾病，由具有扩展多聚谷氨酰胺（polyQ）延伸的突变 HTT（mHTT）蛋白引起。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，并鉴定出四种与 mHTT 和 LC3 相互作用但不与野生型（WT）HTT 相互作用的降低 mHTT 的化合物。这些化合物将 mHTT 靶向到噬菌斑进行自噬降解，而不影响 WT HTT 水平，并挽救 HD 细胞以及果蝇和小鼠 HD 模型中的 HD 相关表型。有趣的是，这些化合物与扩展的 polyQ 延伸直接相互作用，并且能够降低其他具有扩展 polyQ 的致病蛋白。总之，我们的研究为通过 ATTEC 降低 mHTT 提供了初步验证，为 HD 和类似疾病的新治疗策略提供了切入点。
