{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:20:13Z","timestamp":1792804813547,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society of the promotion of Science (JSPS)","award":["21H04816"],"award-info":[{"award-number":["21H04816"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cytopathological hallmark of Parkinson\u2019s disease (PD) is a neuronal cytoplasmic inclusion called Lewy body (LB). Lewy bodies are composed of alpha-synuclein (aSyn), a 140 aa protein that is predominantly expressed in the presynaptic terminal and which is implicated in neurotransmitter release. Recently, aSyn was found to propagate from neuron to neuron in a trans-synaptic manner. Although the precise molecular mechanisms are unclear, the propagation of aSyn is believed to play a major role in the progression of Lewy pathology in PD. Neuropathologically, the initial Lewy pathology has been shown to be formed in the dorsal motor nucleus of the vagus (DMV) or olfactory bulb by neuropathological studies. Since the DMV innervates the enteric nervous system (ENS) and LBs are formed in the gut nerve plexuses, it is conceivable that LBs propagate from the gut to the DMV and then to other regions of the brain. In this article, clinical, neuropathological, and experimental evidence supporting or negating the idea that aSyn propagation from the ENS to the brain leads to PD is reviewed. Moreover, the propagation of aSyn seeds through systemic circulation or multifocal generation of aSyn seeds is discussed as a potential alternative scenario for aSyn spreading<\/jats:p>","DOI":"10.3390\/ijms26093994","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T10:40:48Z","timestamp":1745404848000},"page":"3994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Gut\u2013Brain Axis Based on \u03b1-Synuclein Propagation\u2014Clinical, Neuropathological, and Experimental Evidence"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-9640","authenticated-orcid":false,"given":"Ryosuke","family":"Takahashi","sequence":"first","affiliation":[{"name":"Kyoto University Office of Research Acceleration, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hodaka","family":"Yamakado","sequence":"additional","affiliation":[{"name":"Department of Therapeutics for Multiple System Atrophy, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-0810","authenticated-orcid":false,"given":"Norihito","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Neurological Disease Control, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8475-2589","authenticated-orcid":false,"given":"Tomoyuki","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6436-7923","authenticated-orcid":false,"given":"Jun","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1001\/jamaneurol.2017.3299","article-title":"The Parkinson Pandemic-A Call to Action","volume":"75","author":"Dorsey","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"Alpha-synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1002\/mds.29897","article-title":"Research Priorities on the Role of alpha-Synuclein in Parkinson\u2019s Disease Pathogenesis","volume":"39","author":"Burre","year":"2024","journal-title":"Mov. 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