Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice
Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice
复制标题
传播性α-突触核蛋白病概括了小鼠快速眼动睡眠行为障碍以及帕金森病表型
DOI：
10.1093/brain/awaa283
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发表时间：
2020-11-01
期刊：
影响因子：
14.5
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Shen, Yan;Yu, Wen-Bo;Wang, Jian
特发性快速眼动睡眠行为障碍(RBD)现在被认为是阿尔法突触核病的早期表现。越来越多的实验研究表明，手法损毁或失活被盖背外侧亚核(在人类中也称为蓝斑下核)内的神经元可以在动物中诱导类似RBD的行为。由于目前的RBD动物模型不是建立在α-突触核病的基础上，它们不能代表特发性RBD的病理基础，因此不能模拟向帕金森病的表型转化。因此，这项研究的目的是建立一种基于阿尔法-突触核病的RBD动物模型，该动物模型有可能转化为帕金森病。为此，我们首先确定了野生型C57BL/6J小鼠背侧被盖下核的功能神经解剖学位置，然后基于这个确定的核，通过概括类似RBD的行为来验证其功能。接下来，我们将预制的α-突触核蛋白纤维注射到被盖背侧下核，并对这些小鼠进行常规的多导睡眠图记录以及帕金森病行为和组织病理学研究。因此，我们总结了小鼠的RBD样行为，并进一步表明，背外侧被盖下核中发现的α-突触核病和神经元变性作为神经病理底物。随后的帕金森病行为学研究表明，基于α-突触核病的RBD小鼠模型不是静止的，但可以进一步发展为帕金森病运动障碍、抑郁样障碍、嗅觉障碍和胃肠运动障碍。与此相对应，我们在黑质致密部、嗅球、肠神经丛和迷走神经背侧运动核进行了α-突触核蛋白病理检查，这可能是帕金森病小鼠表现的基础。总之，我们建立了一种新的基于α-突触核病的RBD小鼠模型，并在该动物模型中进一步证明了RBD向帕金森病的表型转化。
Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of alpha-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of alpha-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an alpha-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed alpha-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the alpha-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the alpha-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined alpha-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel alpha-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.