Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases.

中文翻译：

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抑制 MAPK11 或 HIPK3 会降低亨廷顿病模型中突变亨廷顿蛋白的水平。


大多数神经退行性疾病与疾病相关蛋白质的积累有关。其中，亨廷顿病（HD）因其单基因性质而特别令人感兴趣。 HD 主要是由突变亨廷顿基因 (HTT) 编码的缺陷蛋白的细胞毒性引起。因此，降低突变 HTT 蛋白 (mHTT) 水平将是 HD 的一种有前途的治疗策略。在这里，我们报道了两种激酶 HIPK3 和 MAPK11 作为细胞和体内 mHTT 水平的正调节剂。两种激酶均通过其激酶活性调节 mHTT，表明抑制这些激酶可能具有治疗价值。有趣的是，它们对 HTT 水平的影响是 mHTT 依赖性的，提供了一种反馈机制，其中 mHTT 提高其自身水平，从而有助于 mHTT 积累和疾病进展。重要的是，敲除 MAPK11 可显着挽救敲入 HD 小鼠模型中与疾病相关的行为表型。总的来说，我们的数据揭示了 HD 的新治疗切入点和类似疾病的靶点发现方法。