Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
PLoS One. 2013 Dec 20;8(12):e83050. doi: 10.1371/journal.pone.0083050. eCollection 2013.
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of autophagy.
亨廷顿病（HD）是一种致命的神经退行性疾病，由亨廷顿蛋白中扩展的多聚谷氨酰胺重复序列引起。基底神经节和大脑皮层的神经病理学与运动和认知症状有关，而最近的工作表明下丘脑可能与代谢功能障碍有关。几种表现出代谢功能障碍的 HD 小鼠模型存在下丘脑病理学，并且突变型亨廷顿蛋白在下丘脑的表达与小鼠代谢功能障碍的发展有因果关系。尽管突变型亨廷顿蛋白在 HD 脑中发挥其毒性作用的致病机制尚不完全清楚，但有几项研究表明自噬的溶酶体降解途径起作用。有趣的是，下丘脑自噬的变化与野生型小鼠代谢功能障碍的发展有关。我们假设突变型亨廷顿蛋白的表达可能导致代谢功能障碍小鼠下丘脑自噬途径的变化。因此，我们使用重组腺相关病毒载体方法研究了在选择性表达突变型亨廷顿蛋白 853 个氨基酸片段的小鼠模型中，下丘脑自噬途径是否存在变化，以及在代谢功能障碍的转基因 BACHD 小鼠中是否存在变化。我们进行了 qRT-PCR 和 Western blot 来研究选定的自噬标志物的 mRNA 和蛋白表达水平。我们的结果表明，尽管在这两种小鼠模型中都存在代谢功能障碍，但下丘脑的自噬基础水平得到维持。此外，尽管 BACHD 小鼠纹状体和皮层中的自噬没有发生重大变化，但我们在 12 个月大的小鼠中检测到一些标志物的水平有适度但显著的差异。总之，我们的结果表明，突变型亨廷顿蛋白在小鼠中的过表达不会显著扰乱自噬的基础水平。
