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肠道定植的α-突触核蛋白纤维特异性促进老年小鼠的肠道功能障碍和脑部病变。

Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice.

机构信息

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.

出版信息

Nat Neurosci. 2020 Mar;23(3):327-336. doi: 10.1038/s41593-020-0589-7. Epub 2020 Feb 17.

DOI:10.1038/s41593-020-0589-7
PMID:32066981
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7065967/
Abstract

Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson's disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.

摘要

帕金森病是一种突触核蛋白病，其特征是运动功能障碍、中脑多巴胺能神经元死亡和α-突触核蛋白（α-Syn）聚集体的积累。有证据表明，α-Syn 聚集可以起源于外周组织，并通过自主纤维进展到大脑。我们通过将α-Syn 原纤维接种到小鼠的十二指肠壁上来测试这一点。接种后，我们观察到胃肠道功能障碍和肠神经系统的生理变化。使用 AAV-PHP.S 衣壳作为外周基因转移的溶酶体酶葡萄糖脑苷脂酶的靶向物，我们发现由于这种蛋白质的表达增加，α-Syn 病理学减少。最后，将α-Syn 纤维接种到老年小鼠中，但不是年轻小鼠中，导致α-Syn 组织病理学向中脑进展，并随后出现运动缺陷。我们的研究结果描述了前驱期帕金森病的外周突触核蛋白病，并探讨了α-Syn 病理学从肠道到大脑进展的细胞机制。

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