Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease
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DOI：
10.1016/j.nbd.2020.105184
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发表时间：
2021-01-01
影响因子：
6.1
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Marmion, David J.;Rutkowski, Angela A.;Kordower, Jeffrey H.
多系统萎缩症（MSA）是一种罕见且极度衰弱的进行性神经退行性疾病，其特征是帕金森病、小脑性共济失调、自主神经功能障碍和锥体功能障碍的多种组合。 MSA 是一种独特的突触核蛋白病，其中富含 α 突触核蛋白的聚集物存在于少突胶质细胞的细胞质中。在神经胶质细胞质内含物 (GCI) 中发现的 α 突触核蛋白 (aSyn) 的确切起源以及 MSA 中神经变性的机制仍不清楚。尽管如此，MSA 的细胞和动物模型仍然依赖于少突胶质细胞 aSyn 的过度表达。在本研究中，我们利用一种新型寡营养 AAV Olig001 在大鼠和非人灵长类动物的纹状体少突胶质细胞中特异性过度表达 aSyn，以进一步表征我们新型病毒载体介导的 MSA 动物模型。使用 Olig001 载体滴度相差 10 倍的两组动物，我们显示了大鼠中 MSA 样病理的剂量依赖性形成。这些动物需要高滴度的 Olig001-aSyn 来产生 pS129+ 和蛋白酶 K 抗性富含 aSyn 的 GCI、脱髓鞘和神经变性。利用这些知识，我们将高滴度的 Olig001 注射到食蟹猴的壳核中。六个月后，组织学分析表明，aSyn 的少突胶质细胞过度表达导致整个壳核中标志性 GCI 的形成、脱髓鞘、纹状体神经元减少 44% 和黑质神经元损失 12%。此外，Olig001-aSyn NHP 中产生了类似于 MSA 的强烈炎症反应，包括小胶质细胞激活、星形胶质细胞增生和 T 细胞向 CNS 的强烈浸润。总而言之，少突胶质细胞特异性病毒载体介导的 aSyn 在大鼠和非人灵长类动物中的过度表达忠实地再现了 MSA 中发现的许多病理疾病特征。未来利用这些大型 MSA 动物模型进行的研究将证明作为临床前平台非常有价值，可以测试 MSA 急需的新型疗法。
Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In the present study, we utilized a novel oligotrophic AAV, Olig001, to overexpress aSyn specifically in striatal oligodendrocytes of rats and nonhuman primates in an effort to further characterize our novel viral vector-mediated MSA animal models. Using two cohorts of animals with 10-fold differences in Olig001 vector titers, we show a dose-dependent formation of MSA-like pathology in rats. High titer of Olig001-aSyn in these animals were required to produce the formation of pS129+ and proteinase K resistant aSyn-rich GCIs, demyelination, and neurodegeneration. Using this knowledge, we injected high titer Olig001 in the putamen of cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.