Division of Neurobiology, Department of Neurology and Neurosurgery, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
Exp Neurol. 2013 Sep;247:531-6. doi: 10.1016/j.expneurol.2013.02.002. Epub 2013 Feb 8.
Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with limited symptomatic treatment options. Discrimination of MSA from other degenerative disorders crucially depends on the presence of early and severe cardiovascular autonomic failure (CAF). We have previously shown that neuropathologic lesions in the central autonomic nuclei similar to the human disease are present in transgenic MSA mice generated by targeted oligodendroglial overexpression of α-syn using the PLP promoter. We here explore whether such lesions result in abnormalities of heart rate variability (HRV) and circadian rhythmicity which are typically impaired in MSA patients. HRV analysis was performed in five month old transgenic PLP-α-syn (tg) MSA mice and age-matched wild type controls. Decreased HRV and alterations in the circadian rhythmicity were detected in the tg MSA group. The number of choline-acetyltransferase-immunoreactive neurons in the nucleus ambiguus was significantly decreased in the tg group, whereas the levels of arginine-vasopressin neurons in the suprachiasmatic and paraventricular nucleus were not affected. Our finding of impaired HRV and circadian rhythmicity in tg MSA mice associated with degeneration of the nucleus ambiguus suggests that a cardinal non-motor feature of human MSA can be reproduced in the mouse model strengthening its role as a valuable testbed for studying selective vulnerability and assessing translational therapies.
多系统萎缩（MSA）是一种致命的、快速进展的神经退行性疾病，其治疗选择有限。将 MSA 与其他退行性疾病区分开来，关键取决于是否存在早期和严重的心血管自主神经衰竭（CAF）。我们之前已经表明，在使用 PLP 启动子靶向少突胶质细胞过表达α-突触核蛋白产生的转基因 MSA 小鼠中，存在与人类疾病相似的中枢自主核内神经病变。我们在这里探讨这些病变是否导致心率变异性（HRV）和昼夜节律的异常，而这些异常通常在 MSA 患者中受到损害。在五个月大的转基因 PLP-α-突触核蛋白（tg）MSA 小鼠和年龄匹配的野生型对照中进行了 HRV 分析。在 tg MSA 组中检测到 HRV 降低和昼夜节律改变。tg 组的疑核中胆碱乙酰转移酶免疫反应性神经元数量显著减少，而视交叉上核和室旁核中的精氨酸加压素神经元水平没有受到影响。我们发现 tg MSA 小鼠的 HRV 和昼夜节律受损与疑核退化有关，这表明人类 MSA 的一个主要非运动特征可以在小鼠模型中重现，这增强了其作为研究选择性易损性和评估转化治疗的有价值的试验台的作用。
