Limited spread of pathology within the brainstem of α-synuclein BAC transgenic mice inoculated with preformed fibrils into the gastrointestinal tract.
Limited spread of pathology within the brainstem of α-synuclein BAC transgenic mice inoculated with preformed fibrils into the gastrointestinal tract.
复制标题
将预先形成的原纤维接种到胃肠道的 α-突触核蛋白 BAC 转基因小鼠的脑干内病理学的有限传播。
DOI：
10.1016/j.neulet.2019.134651
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Takahashi R.
中科院分区：
文献类型：
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作者：
Uemura N;Yagi H;Uemura MT;Yamakado H;Takahashi R.
帕金森病（Parkinson's disease，PD）的病理特征是神经元内α-突触核蛋白（α-synuclein，α-Syn）聚集，称为Lewy小体（Lewy bodies，LB），以及黑质腹侧部多巴胺能神经元（substantia nigra pars reticulta，SNpc）的缺失。根据尸检研究，Braak等人假设路易病最初发生在肠神经系统，随后扩散至迷走神经背侧运动核（dmX），然后在脑干中上升至SNpc。然而，这种假设的进展缺乏足够的实验证据。我们以前报道过，将α-Syn预形成的纤维（PFF）接种到野生型（WT）小鼠的胃壁中，诱导了在dmXvitamin迷走神经中的LB样α-Syn聚集体。然而，α-Syn病理学在接种后12个月内没有扩散到dmX之外。在本研究中，我们将α-Syn PFF接种到携带A53 T突变的人α-Syn基因的细菌人工染色体（BAC）转基因小鼠的胃壁中，并分析病理学。与WT小鼠相比，转基因小鼠脑中α-Syn过表达为WT小鼠的1.5倍，胃中α-Syn过表达为WT小鼠的1.6倍。在接种α-Syn PFF后，与类似接种的WT小鼠相比，转基因小鼠在dmX中产生了更多的磷酸化α-Syn（p-α-Syn）阳性神经元。但dmX区的p-α-Syn阳性神经元数量随时间而减少，除疑核外，其他脑区在接种后8个月未观察到α-Syn病理变化。综上所述，BAC转基因表达α-Syn促进了脑干中α-Syn病理学的诱导，但与Braak的假设一致，没有促进随后的尾吻侧扩散。
Parkinson’s disease (PD) is pathologically characterized by intraneuronal α-synuclein (α-Syn) aggregates called Lewy bodies (LBs) as well as the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). On the basis of autopsy studies, Braak et al. hypothesized that Lewy pathology initially occurs in the enteric nervous system, subsequently spreading to the dorsal motor nucleus of the vagus nerve (dmX) and then ascending in the brainstem to the SNpc. However, this hypothetical progression lacks adequate experimental evidence. We previously reported that inoculation of α-Syn preformed fibrils (PFFs) into the gastric wall of wild-type (WT) mice induced LB-like α-Syn aggregates in the dmXviathe vagus nerve. However, α-Syn pathology did not spread beyond the dmX up to 12 months postinoculation. In the present study, we inoculated α-Syn PFFs into the gastric wall of bacterial artificial chromosome (BAC) transgenic mice harboring the human α-Syn gene with an A53 T mutation and analyzed the pathology. The transgenic mice had ∼1.5-fold overexpression of α-Syn in the brains and ∼6-fold overexpression of α-Syn in the stomach compared with WT mice. After inoculation of α-Syn PFFs, the transgenic mice developed a higher number of phosphorylated α-Syn (p-α-Syn)–positive neurons in the dmX compared with similarly inoculated WT mice. However, the number of p-α-Syn–positive neurons in the dmX decreased over time, and α-Syn pathology was not observed in other brain regions except in the ambiguous nucleus up to 8 months postinoculation. Taken together, BAC transgenic expression of α-Syn facilitated induction of α-Syn pathology in the brainstem, but not subsequent caudo-rostral spread in accordance with Braak’s hypothesis.