MassGeneral Institute for Neurodegenerative Disease and Harvard Medical School, Charlestown, MA, USA.
Mol Neurodegener. 2010 Jun 22;5:26. doi: 10.1186/1750-1326-5-26.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD.
Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels.
Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.
亨廷顿病（HD）是一种进行性神经退行性疾病，由亨廷顿基因内 CAG 重复扩展引起。突变亨廷顿蛋白错误折叠并在神经元内积累，在那里介导其毒性作用。通过激活巨自噬促进突变亨廷顿清除是治疗亨廷顿病（HD）的一种方法。在这项研究中，我们评估了雷帕霉素（mTOR 激酶抑制剂和巨自噬促进药物）在 R6/2 亨廷顿病小鼠模型中的作用。
雷帕霉素降低了 mTOR 靶蛋白 S6 激酶的磷酸化，表明其穿透大脑。然而，雷帕霉素并没有像通过 LC3B Western blot 分析所测量的那样激活大脑巨自噬。雷帕霉素可预防运动功能的早期下降；然而，我们没有发现脑病理学确定的神经保护证据。在肌肉中，但不是在大脑中，雷帕霉素显著降低了可溶性突变亨廷顿蛋白的水平。
我们的数据表明，雷帕霉素在 R6/2 小鼠中的有益行为效应主要来自对肌肉的影响。尽管雷帕霉素显著调节其大脑 S6 激酶的靶标，但这并没有降低突变亨廷顿蛋白的水平或提供神经保护。
