构建α-突触核蛋白异构体诱导食蟹猴多系统萎缩模型及相关机制研究

The common pathogenesis of α-synucleinopathies is formation and propagation of α-synuclein (α-syn) positive inclusions in central nervous system. α-Syn positive inclusions are not evenly distributed in central nervous system, but affect the certain type of cells and regions, and induce the different symptoms. Multiple system atrophy (MSA) is a kind of rapidly progressive α-synucleinopathies with poor prognosis. Autonomic dysfunctions, such as sexual dysfunction and uropoiesis dysfunction, are main symptoms of MSA. So far, animal models of MSA are mainly toxicant-induced model or transgenic animal model, and all of the models only displayed the movement dysfunction of MSA. Our previous study suggested that before the movement dysfunction onset, α-syn positive inclusions were detected in the bladders of MSA. Then we established an SD rat model, which α-syn positive inclusions spreaded from genitourinary autonomic pathways to brain, and induced the symptoms of MSA. In this research project, we plan to established the first non-toxic,non-transgenic, α-syn strains induced cynomolgus macaque model for MSA. We will try to establishes a batter platform for study the pathogenesis of MSA in primate.

α-synuclein（α-syn）阳性包涵体在神经系统形成及播散是α-突触核蛋白病共同病理特征。α-syn阳性包涵体选择性累及神经系统特定区域导致不同疾病症候群。多系统萎缩（MSA）是一种进展迅速、预后差的α-突触核蛋白病。以泌尿及性功能障碍为主的自主神经障碍是其主要临床表现。目前MSA动物模型均为神经毒物或转基因模型，仅展现MSA部分病理改变及运动症状。本项目前期研究发现：运动障碍出现前MSA患者膀胱已有α-syn阳性包涵体沉积。进一步构建α-syn阳性包涵体从膀胱肌层神经末梢沿泌尿生殖相关自主神经通路逆行播散至大脑的大鼠MSA模型，成功模拟MSA自主神经功能障碍及运动障碍。此结果提示：α-syn阳性包涵体沿泌尿生殖相关自主神经通路逆行播散可能导致MSA症候群。本项目拟构建国内外首例非毒物、非转基因、α-syn蛋白异构体诱导食蟹猴MSA模型，为探索灵长类MSA致病机制提供更好平台。

多系统萎缩（multiple system atrophy，MSA）是神经退行性疾病的一种，以自主神经功能障碍、左旋多巴非敏感性帕金森症状及小脑性共济失调为特征性临床表现，该病早期诊断极为困难，目前尚无有效治疗方法，平均存活期仅为5-6 年，至今为止该病致病机制仍不明。α-synuclein（α-syn）阳性包涵体沉积在中枢神经系统少突胶质细胞内是此病特征性病理标志。越来越多的体外研究发现α-syn 可以“朊蛋白”的致病模式在细胞中形成包涵体并播散。寻找不同α-突触核蛋白病α-syn 阳性包涵体播散特异性的神经传导通路，构建不同α-突触核蛋白病的非人灵长类动物模型，是研究α-突触核蛋白病的病理机制。本研究发现：MSA患者病程早期膀胱肌层神经末梢已形成α-syn 阳性包涵体，进一步构建大鼠模型证实α-syn 阳性包涵体可沿泌尿生殖相关自主神经通路逆行播散至大脑并模拟 MSA 运动及排尿障碍。以此作为基础，进一步研究发现α-syn 阳性包涵体可从膀胱肌层神经纤维末梢沿泌尿生殖相关自主神经通路（膀胱肌层、盆丛、IML、Onuf 核、脑桥被盖、基底节区）逆行播散至大脑，并导致 MSA 症候群，如自主神经功能障碍及运动障碍等，同时成功构建了国内外首例非毒物、非转基因、非人灵长类 MSA 模型，为揭示 MSA 的病理机制，寻找阻止 MSA 的病程进展的特异性分子靶标建立更为优化的动物模型。