Initiation of Parkinson's disease from gut to brain by δ-secretase

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2020,（1）
• 页码范围: 70-87
• 页数: 18页
• 语种: 英文
• DOI: 10.1038/s41422-019-0241-9

摘要

Lewy pathology,composed of α-Synuclein (α-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 δ-secretase (asparagine endopeptidase,AEP) cleaves both α-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.α-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 α-Syn N103/Tau N368 complex formation in the gut,eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner.Preformed fibrils (PFFs) of α-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,δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.