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Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of \u03b1-synuclein aggregates, which may not only enhance cell death but also contribute to disease progression by seeding the formation of additional aggregates in neighbouring cells. The mechanisms driving intercellular transmission of aggregates remain unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular aquaporin-4 localization, inhibits \u03b1-synuclein clearance and facilitates \u03b1-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical \u03b1-synuclein pathology was associated with aquaporin-4 mis-localization throughout the grey matter. Using a transgenic mouse model lacking the adapter protein \u03b1-syntrophin, we observed that loss of perivascular aquaporin-4 localization impairs the glymphatic clearance of \u03b1-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of \u03b1-synuclein propagation using pre-formed fibril injection, we observed that loss of perivascular aquaporin-4 localization increased \u03b1-synuclein aggregates. Our results indicate \u03b1-synuclein clearance and propagation are mediated by glymphatic function and that aquaporin-4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy body dementia and Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag327","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:01:51Z","timestamp":1787770911000},"source":"Crossref","is-referenced-by-count":1,"title":["Aquaporin-4 mis-localization decreases glymphatic clearance of \u03b1-synuclein in an alpha-syntrophin knock out mouse model and promotes \u03b1-synuclein pathology and aggregate propagation"],"prefix":"10.1093","volume":"8","author":[{"given":"Molly","family":"Braun","sequence":"first","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]},{"name":"Department of Neurosurgery, Medical College of Georgia, Augusta University , Augusta, GA 30912 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]},{"name":"Neuroscience Graduate Program, Oregon Health & Science University School of Medicine , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Jang","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Sanderson","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Swierz","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Sevao","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra B","family":"Pincus","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, Oregon Health & Science University School of Medicine , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison J","family":"Schaser","sequence":"additional","affiliation":[{"name":"Jungers Center for Neuroscience Research, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6992-6851","authenticated-orcid":false,"given":"Jonathan E","family":"Elliott","sequence":"additional","affiliation":[{"name":"VA Portland Health Care System , Portland, OR 97239 ,","place":["USA"]},{"name":"Department of Neurology, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3876-3196","authenticated-orcid":false,"given":"Miranda M","family":"Lim","sequence":"additional","affiliation":[{"name":"VA Portland Health Care System , Portland, OR 97239 ,","place":["USA"]},{"name":"Department of Neurology, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek K","family":"Unni","sequence":"additional","affiliation":[{"name":"Jungers Center for Neuroscience Research, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]},{"name":"Department of Neurology, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail G","family":"Schindler","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]},{"name":"VISN 20 Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin S","family":"Latimer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J","family":"Iliff","sequence":"additional","affiliation":[{"name":"VISN 20 Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]},{"name":"Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]},{"name":"Department of Neurology, University of Washington School of Medicine , Seattle, WA 98195 ,","place":["USA"]},{"name":"Knight Cardiovascular Institute, Oregon Health & Science University , Portland, OR 97239 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"issue":"6315","key":"2026090803363726800_fcag327-B1","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1126\/science.aah4968","article-title":"Mechanisms linking circadian clocks, sleep, and neurodegeneration","volume":"354","author":"Musiek","year":"2016","journal-title":"Science"},{"issue":"7465","key":"2026090803363726800_fcag327-B2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of 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