ArticleCell research2020
Initiation of Parkinson's disease from gut to brain by δ-secretase.
Article in Cell research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 4 of them syntheses that pooled it.
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The trial behind it
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Who cites it
68 citing papers in PubMed, 4 syntheses or guidelines pooled it, 102 citations in OpenAlex.
- Enteric Nervous System Damage by Food Contaminants: A Pathway to Neurodegeneration?Comprehensive reviews in food science and food safety · 2026Pooled it
- Possible linking and treatment between Parkinson's disease and inflammatory bowel disease: a study of Mendelian randomization based on gut-brain axis.Journal of translational medicine · 2025Pooled it
- Experimental models of gut-first Parkinson's disease: A systematic review.Neurogastroenterology and motility · 2023Pooled it
- Hypoxia and Alpha-Synuclein: Inextricable Link Underlying the Pathologic Progression of Parkinson's Disease.Frontiers in aging neuroscience · 2022Pooled it
- Brain-first versus body-first Parkinson's disease: Differential findings on pupillary, brainstem and vagus sonography.Journal of neurology · 2026Article
- Brain-Only Versus GI-Only Synucleinopathy: A Comprehensive Autopsy Study With Both IHC and SAA.medRxiv : the preprint server for health sciences · 2026Article
- Parkinson's Disease: The Epidemiology, Risk Factors, Molecular Pathogenesis, Prevention, and Therapy.MedComm · 2025Review
- Netrin-1 Inhibits Neuroinflammation by Modulating DRD2/GSK3β Signaling and Suppressing ROS in a Parkinson's Disease Model.CNS neuroscience & therapeutics · 2025Article
- C-terminus-dependent detection of lysosomal alpha-synuclein in nigral Parkinson's disease human brain neurons.Molecular neurodegeneration · 2025Article
- Converging pathologies in neurodegeneration: the mechanistic interplay between α-Synuclein and Tau in Alzheimer's and Parkinson's.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Impact of α-synuclein fibril structure on seeding activity in experimental models of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Repurposing the memory-promoting meclofenoxate hydrochloride as a treatment for Parkinson's disease through integrative multi-omics analysis.NPJ Parkinson's disease · 2025Article
- Article
- Disruption of axonal transport in Parkinson's disease: the role of pathological α-Syn and AMPK/p38 MAPK signaling.NPJ Parkinson's disease · 2025Article
- Distribution of gut microbiota across intestinal segments and their impact on human physiological and pathological processes.Cell & bioscience · 2025Review
- Article
- Netrin-1 signaling pathway mechanisms in neurodegenerative diseases.Neural regeneration research · 2025Article
- Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury.Materials today. Bio · 2025Article
- Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson's disease.Nature neuroscience · 2025Article
- Rotenone Induces Parkinsonism with Constipation Symptoms in Mice by Disrupting the Gut Microecosystem, Inhibiting the PI3K-AKT Signaling Pathway and Gastrointestinal Motility.International journal of molecular sciences · 2025Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.