Nature子刊:帕金森病起源于肠道的新发现
创作:orchid 审核:mildbreeze 03月04日
  • 将α-突触核蛋白(α-Syn)预制原纤维(PFF)接种到小鼠十二指肠壁,可引起肠神经中致病性α-Syn聚集,破坏肠神经连接,引起胃肠功能障碍和炎症反应;
  • 致病性α-Syn积累可抑制降解α-Syn的溶酶体酶葡萄糖苷脂酶(GCase)生成,用AAV载体在外周神经中表达编码GCase的基因GBA1,可减轻α-Syn病理;
  • 老年(而非年轻)小鼠中,在肠道接种α-Syn PFF可引起α-Syn病理从肠道发展至脑干,并导致运动缺陷,可能与老年小鼠GCase生成不足有关。
主编推荐语
mildbreeze
突触核蛋白病(synucleinopathy)是一种神经退行性疾病,以不溶性的淀粉样α-突触核蛋白(α-Syn)原纤维在神经中的聚集为特征,比如帕金森病就是这类疾病的典型代表。有证据显示,α-Syn的聚集可能是起始于肠道,而后经自主神经纤维传递至脑部。Nature Neuroscience近期发表的一项研究对这一假说进行了检验,通过小鼠试验表明,α-Syn原纤维可破坏肠神经系统,引起肠道功能障碍和炎症,而用AAV(腺相关病毒)载体在外周组织表达GBA1基因(编码降解α-Syn的酶)可部分缓解α-Syn病理。此外研究者还发现,α-Syn从肠至脑的病理发展与年龄有关,老年小鼠比年轻小鼠更为易感。这些发现加深了对突触核蛋白病发病机理的认知,强调了疾病早期将诊断和干预聚焦于肠道的重要性,为治疗这类疾病提供了新思路。
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Nature Neuroscience [IF:20.071]

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

肠道接种的α-突触核蛋白(α-Syn)原纤维促进老年小鼠的肠道功能障碍和脑病理

10.1038/s41593-020-0589-7

02-17, Article

Abstract & Authors:展开

Abstract:收起
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.

First Authors:
Collin Challis

Correspondence Authors:
Viviana Gradinaru

All Authors:
Collin Challis,Acacia Hori,Timothy R Sampson,Bryan B Yoo,Rosemary C Challis,Adam M Hamilton,Sarkis K Mazmanian,Laura A Volpicelli-Daley,Viviana Gradinaru

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