Initiation of Parkinson's disease from gut to brain by δ-secretase
Initiation of Parkinson's disease from gut to brain by δ-secretase
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DOI：
10.1038/s41422-019-0241-9
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发表时间：
2020-01-01
期刊：
影响因子：
44.1
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
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作者：
Ahn, Eun Hee;Kang, Seong Su;Ye, Keqiang
路易病理学由 α-突触核蛋白 (α-Syn) 内含物组成，是帕金森病 (PD) 的标志，逐渐从肠神经系统 (ENS) 扩散到中枢神经系统 (CNS)。然而，目前尚不清楚这一过程是如何在分子水平上调控的。在这里，我们表明，δ-分泌酶（天冬酰胺内肽酶，AEP）可裂解 N103 处的 α-Syn 和 N368 处的 Tau，并介导它们的原纤维化和从肠道到大脑的逆行传播，引发与路易体和运动功能障碍相关的黑质多巴胺能神经元损失。 α-Syn N103 和 Tau N368 彼此强烈相互作用，并且在 PD 患者的肠道和大脑中高度升高。长期口服神经毒素鱼藤酮会诱导 AEP 激活并在肠道内形成 α-Syn N103/Tau N368 复合物，从而以 AEP 依赖性方式引发便秘和多巴胺能神经元死亡。 α-Syn N103/Tau N368 的预制原纤维 (PFF) 具有更强的神经毒性和致密性，并且比 FL/FL 对应物或单个片段的原纤维沿着迷走神经聚集得更快。结肠注射 PFF 会诱发 PD 病理、运动功能障碍和认知障碍。因此，δ-分泌酶在引发从 ENS 到 CNS 的 PD 病理进展中起着至关重要的作用。
Lewy pathology, composed of alpha-Synuclein (alpha-Syn) inclusions, a hallmark of Parkinson's disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that delta-secretase (asparagine endopeptidase, AEP) cleaves both alpha-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. alpha-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients' gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and alpha-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of alpha-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments' fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, delta-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.