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

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Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41593-020-0589-7
Collin Challis ₁ , Acacia Hori ₁ , Timothy R Sampson _{1,

2} , Bryan B Yoo ₁ , Rosemary C Challis ₁ , Adam M Hamilton ₂ , Sarkis K Mazmanian ₁ , Laura A Volpicelli-Daley ₃ , Viviana Gradinaru ₁

Affiliation

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.

中文翻译：

肠道种子 α-突触核蛋白原纤维会促进肠道功能障碍和大脑病理，特别是在老年小鼠中。

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，并通过自主神经纤维进展到大脑。我们通过用 α-Syn 预形成原纤维接种小鼠十二指肠壁来对此进行测试。接种后，我们观察到胃肠道缺陷和肠神经系统的生理变化。使用 AAV-PHP.S 衣壳靶向溶酶体酶葡萄糖脑苷脂酶进行外周基因转移，我们发现由于该蛋白表达增加，α-Syn 病理学减少。最后，在老年小鼠而非年轻小鼠中接种 α-Syn 原纤维，会导致 α-Syn 组织病理学进展到中脑以及随后的运动缺陷。我们的结果描述了前驱帕金森病的外周突触核蛋白病的特征，并探索了 α-Syn 病理学从肠道到大脑进展的细胞机制。

更新日期：2020-02-17

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