Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, USA and Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.
Metallomics. 2020 Jul 22;12(7):1118-1130. doi: 10.1039/d0mt00081g.
Manganese (Mn) is an essential micronutrient required for the proper function of several enzymes. Accumulating evidence demonstrates a selective decrease of bioavailable Mn in vulnerable cell types of Huntington's Disease (HD), an inherited progressive neurodegenerative disorder with no cure. Amelioration of underlying pathophysiology, such as alterations in Mn-dependent biology, may be therapeutic. We therefore sought to investigate global Mn-dependent and Mn-responsive biology following various Mn exposures in a mouse model of HD. YAC128 and wildtype (WT) littermate control mice received one of three different Mn exposure paradigms by subcutaneous injection of 50 mg kg-1 MnCl2·4(H2O) across two distinct HD disease stages. "Pre-manifest" (12-week old mice) mice received either a single (1 injection) or week-long (3 injections) exposure of Mn or vehicle (H2O) and were sacrificed at the pre-manifest stage. "Manifest" (32-week old) mice were sacrificed following either a week-long Mn or vehicle exposure during the manifest stage, or a 20-week-long chronic (2× weekly injections) exposure that began in the pre-manifest stage. Tissue Mn, mRNA, protein, and metabolites were measured in the striatum, the brain region most sensitive to neurodegeneration in HD. Across all Mn exposure paradigms, pre-manifest YAC128 mice exhibited a suppressed response to transcriptional and protein changes and manifest YAC128 mice showed a suppressed metabolic response, despite equivalent elevations in whole striatal Mn. We conclude that YAC128 mice respond differentially to Mn compared to WT as measured by global transcriptional, translational, and metabolomic changes, suggesting an impairment in Mn homeostasis across two different disease stages in YAC128 mice.
锰（Mn）是几种酶正常功能所必需的微量元素。越来越多的证据表明，亨廷顿病（HD）脆弱细胞类型中生物可利用的锰含量选择性降低，而 HD 是一种无法治愈的遗传性进行性神经退行性疾病。改善潜在的病理生理学，如依赖锰的生物学改变，可能具有治疗作用。因此，我们试图在 HD 的小鼠模型中研究各种锰暴露后，全基因组依赖锰和对锰响应的生物学变化。YAC128 和野生型（WT）同窝对照小鼠通过皮下注射 50mgkg-1 MnCl2·4（H2O）接受三种不同的锰暴露方案之一，跨越两个不同的 HD 疾病阶段。“前发病”（12 周龄的小鼠）接受单次（1 次注射）或为期一周（3 次注射）的锰或载体（H2O）暴露，然后在发病前阶段处死。“发病”（32 周龄）小鼠在发病阶段接受一周的锰或载体暴露后或在发病前阶段开始的 20 周慢性（2×每周注射）暴露后处死。纹状体中测量了组织锰、mRNA、蛋白质和代谢物，纹状体是 HD 中最易发生神经退行性变的大脑区域。在所有锰暴露方案中，发病前的 YAC128 小鼠表现出对转录和蛋白质变化的反应受到抑制，而发病的 YAC128 小鼠表现出代谢反应受到抑制，尽管整个纹状体锰的升高幅度相同。我们得出结论，与 WT 相比，YAC128 小鼠对锰的反应不同，这可以通过全基因组转录、翻译和代谢组学变化来衡量，表明 YAC128 小鼠在两个不同的疾病阶段存在锰稳态的损害。
