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Although \u03b1-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of \u03b1-synuclein in Krabbe\u2019s disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of \u03b1-synuclein in KD. While genetic knock-out of \u03b1-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents \u03b1-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of \u03b1-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open\/aggregation-prone conformation of \u03b1-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed\/aggregation-resistant conformation of \u03b1-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in \u03b1-synucleinopathies, and provide a mechanistic understanding of \u03b1-synuclein aggregation in glycosphingolipidoses.<\/jats:p>","DOI":"10.1038\/s41598-018-30808-9","type":"journal-article","created":{"date-parts":[[2018,8,14]],"date-time":"2018-08-14T14:16:53Z","timestamp":1534256213000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["\u03b1-Synuclein interacts directly but reversibly with psychosine: implications for \u03b1-synucleinopathies"],"prefix":"10.1038","volume":"8","author":[{"given":"Hazem","family":"Abdelkarim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5742-2031","authenticated-orcid":false,"given":"Michael S.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Scesa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Rue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vince","family":"Elackattu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Stoskute","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazan","family":"Issa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zane","family":"Hauck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2016-0063","authenticated-orcid":false,"given":"Richard","family":"van Breemen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria S.","family":"Celej","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vadim","family":"Gaponenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesto R.","family":"Bongarzone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,8,20]]},"reference":[{"key":"30808_CR1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1002\/path.4328","volume":"232","author":"BR Smith","year":"2014","unstructured":"Smith, B. 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