{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:16:58Z","timestamp":1788430618655,"version":"build-2803163510"},"reference-count":69,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Misfolding and aggregation of \u03b1\u2010Synuclein (\u03b1\u2010Syn) play a central role in Parkinson's disease (PD), with oligomeric intermediates implicated as key toxic species. Here, we investigate the aggregation of two \u03b1\u2010Syn segments, the NACore (\n                      <jats:sub>68<\/jats:sub>\n                      GAVVTGVTAVA\n                      <jats:sub>78<\/jats:sub>\n                      , WT\u2010PD1) and the preNAC region (\n                      <jats:sub>47<\/jats:sub>\n                      GVVHGVATVA\n                      <jats:sub>56<\/jats:sub>\n                      , WT\u2010PD2), using high\u2010resolution trapped ion\u2010mobility mass spectrometry (TIMS\u2010Qq\u2010ToF) and Thioflavin\u00a0T fluorescence spectroscopy. The NACore is the minimal sequence required for \u03b1\u2010Syn aggregation, whereas most mutations affecting the onset of PD appear to be in the preNAC region, therefore modulating aggregation dynamics and toxicity. Our results demonstrate that TIMS\u2010Qq\u2010ToF effectively resolves and identifies oligomeric species, revealing distinct aggregation pathways for both peptide segments. Fluorescence assays confirm differences in aggregation kinetics and morphology, highlighting the different oligomer formation pathways observed with ion\u2010mobility mass spectrometry. Despite the oligomer\u2010preserving nature of the TIMS itself, ion transmission remains too harsh for the fragile oligomers, leading to fragmentation of fragile non\u2010covalent assemblies. However, collisional cross\u2010section (\n                      <jats:sup>N2<\/jats:sup>\n                      CCS\n                      <jats:sub>TIMS<\/jats:sub>\n                      ) values support the presence of large oligomers. This study highlights the potential of TIMS\u2010Qq\u2010ToF for mapping \u03b1\u2010Syn aggregation and underscores the need for optimised, soft ion transmission to better preserve fragile transient intermediates, ultimately contributing to a deeper understanding of PD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Understanding early\u2010stage protein aggregation is essential for unravelling the molecular mechanisms of Parkinson's disease, a neurodegenerative disorder that currently lacks effective therapeutic solutions. This study employs high\u2010resolution Trapped Ion Mobility Mass Spectrometry combined with fluorescence spectroscopy to elucidate the oligomerisation of two \u03b1\u2010synuclein segments, revealing distinct aggregation pathways and associated structural characteristics. This study underscores the value of peptide models in advancing our understanding of protein aggregation behaviour. This multifaceted approach provides detailed structural insights into the unexplored, transient early\u2010stage oligomers of key \u03b1\u2010Syn segments, contributing to a deeper understanding of aggregation mechanisms and providing valuable insights for therapeutic strategies against Parkinson's disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pmic.70087","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T10:47:04Z","timestamp":1765363624000},"page":"49-59","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Probing Early \u03b1\u2010Synuclein Oligomers: Insights Into Aggregation Pathways of NACore and preNAC Segments Probed by Trapped Ion\u2010Mobility Mass Spectrometry and Fluorescence Spectroscopy"],"prefix":"10.1002","volume":"26","author":[{"given":"Agathe Depraz","family":"Depland","sequence":"first","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Division of Bioanalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Centre for Analytical Chemistry Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Mikromanolis","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Division of Bioanalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia","family":"Stroganova","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Division of Bioanalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Centre for Analytical Chemistry Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7446-9907","authenticated-orcid":false,"given":"Anouk M.","family":"Rijs","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmaceutical Sciences, Division of Bioanalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences Vrije Universiteit Amsterdam  Amsterdam the Netherlands"},{"name":"Centre for Analytical Chemistry Amsterdam  Amsterdam the 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