{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:12:06Z","timestamp":1790878326464,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,7]],"date-time":"2021-03-07T00:00:00Z","timestamp":1615075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["Projects G.0927.14, G080517N and SBO S006617N Neuro-TRAFFIC"],"award-info":[{"award-number":["Projects G.0927.14, G080517N and SBO S006617N Neuro-TRAFFIC"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","award":["OT\/14\/120, C14\/18\/102, DBOF fellowship to Jianmin Si"],"award-info":[{"award-number":["OT\/14\/120, C14\/18\/102, DBOF fellowship to Jianmin Si"]}],"id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the ERA-NET JPco-fuND 2015 SYNACTION","award":["JPND-SYNACTION-ANR-15-JPWG-0012-03"],"award-info":[{"award-number":["JPND-SYNACTION-ANR-15-JPWG-0012-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>ATP13A2, a late endo-\/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson\u2019s disease and Kufor\u2013Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine\/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of \u03b1-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to \u03b1-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces \u03b1-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on \u03b1-synuclein multimerization, which corresponded with reduced \u03b1syn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of \u03b1-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of \u03b1-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on \u03b1-synuclein multimerization via polyamine transport dependent and independent functions.<\/jats:p>","DOI":"10.3390\/ijms22052689","type":"journal-article","created":{"date-parts":[[2021,3,7]],"date-time":"2021-03-07T20:20:43Z","timestamp":1615148443000},"page":"2689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["ATP13A2 Regulates Cellular \u03b1-Synuclein Multimerization, Membrane Association, and Externalization"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9026-4226","authenticated-orcid":false,"given":"Jianmin","family":"Si","sequence":"first","affiliation":[{"name":"Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Van den Haute","sequence":"additional","affiliation":[{"name":"Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium"},{"name":"Leuven Viral Vector Core, Division Molecular Medicine, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evy","family":"Lobbestael","sequence":"additional","affiliation":[{"name":"Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Martin","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, Bus 802, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"van Veen","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, Bus 802, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-2944","authenticated-orcid":false,"given":"Peter","family":"Vangheluwe","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, Bus 802, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerle","family":"Baekelandt","sequence":"additional","affiliation":[{"name":"Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,7]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and Treatment of Parkinson Disease: A Review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/nrneurol.2012.242","article-title":"100 years of Lewy pathology","volume":"9","author":"Goedert","year":"2013","journal-title":"Nat. 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