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Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of sulfation. Heparin, a highly sulfated glycosaminoglycan, is a relevant mimic for mature heparan sulfate and has been shown to influence aSN fibrillation. Here, we decompose the underlying properties of the interaction between heparin and aSN and the effect of heparin on fibrillation. Via the isolation of the first 61 residues of aSN, which lacked intrinsic fibrillation propensity, fibrillation could be induced by heparin, and access to the initial steps in fibrillation was possible. Here, structural changes with shifts from disorder via type I \u03b2-turns to \u03b2-sheets were revealed, correlating with an increase in the aSN1\u201361\/heparin molar ratio. Fluorescence microscopy revealed that heparin and aSN1\u201361 co-exist in the final fibrils. We conclude that heparin can induce the fibrillation of aSN1\u201361, through binding to the N-terminal with an affinity that is higher in the truncated form of aSN. It does so by specifically modulating the structure of aSN via the formation of type I \u03b2-turn structures likely critical for triggering aSN fibrillation.<\/jats:p>","DOI":"10.3390\/biom10081192","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T04:35:51Z","timestamp":1597638951000},"page":"1192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Non-Fibrillating N-Terminal of \u03b1-Synuclein Binds and Co-Fibrillates with Heparin"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-6143","authenticated-orcid":false,"given":"Line K.","family":"Skaanning","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-907X","authenticated-orcid":false,"given":"Angelo","family":"Santoro","sequence":"additional","affiliation":[{"name":"Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maal\u00f8es vej 5, 2200 Copenhagen N, Denmark"},{"name":"Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Skamris","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9874-1138","authenticated-orcid":false,"given":"Jacob Hertz","family":"Martinsen","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"},{"name":"Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maal\u00f8es vej 5, 2200 Copenhagen N, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"D\u2019Ursi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7612-223X","authenticated-orcid":false,"given":"Saskia","family":"Bucciarelli","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bente","family":"Vestergaard","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-6243","authenticated-orcid":false,"given":"Katrine","family":"Bugge","sequence":"additional","affiliation":[{"name":"Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maal\u00f8es vej 5, 2200 Copenhagen N, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2467-4205","authenticated-orcid":false,"given":"Annette Eva","family":"Langkilde","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7454-1761","authenticated-orcid":false,"given":"Birthe B.","family":"Kragelund","sequence":"additional","affiliation":[{"name":"Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maal\u00f8es vej 5, 2200 Copenhagen N, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature16531","article-title":"Structural disorder of monomeric \u03b1-synuclein persists in mammalian cells","volume":"530","author":"Theillet","year":"2016","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1017\/S0033583516000172","article-title":"Secondary nucleation of monomers on fibril surface dominates \u03b1-synuclein aggregation and provides autocatalytic amyloid amplification","volume":"50","author":"Gaspar","year":"2017","journal-title":"Q. 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