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Here, we show that \u03b1-synuclein pre-formed fibrils trigger a reorganization of voltage-gated calcium (Ca\n                  <jats:sub>V<\/jats:sub>\n                  ) channels in cultured mouse cortical neurons, increasing their clustering at the soma and dendrites. We find that \u03b1-synuclein fibrils promote cyclin-dependent kinase 5\u2013mediated phosphorylation of K\n                  <jats:sub>V<\/jats:sub>\n                  2.1 at serine 603, enhancing its scaffolding capacity for Ca\n                  <jats:sub>V<\/jats:sub>\n                  channels. Disrupting Ca\n                  <jats:sub>V<\/jats:sub>\n                  \u2013K\n                  <jats:sub>V<\/jats:sub>\n                  2.1 coupling with a competitive peptide or pharmacological CDK5 inhibition restores channel proximity to control levels. Functionally, the enhanced Ca\n                  <jats:sub>V<\/jats:sub>\n                  clustering amplifies depolarization-evoked Ca\n                  <jats:sup>2+<\/jats:sup>\n                  influx and drives aberrant excitation\u2013transcription coupling, as reflected by elevated expression of the immediate early gene c-Fos. All effects were rescued by disrupting Ca\n                  <jats:sub>V<\/jats:sub>\n                  \u2013K\n                  <jats:sub>V<\/jats:sub>\n                  2.1 interactions or inhibiting Ca\n                  <jats:sub>V<\/jats:sub>\n                  channel activity. These findings identify nanoscale Ca\n                  <jats:sub>V<\/jats:sub>\n                  channel remodeling as a mechanistic link between \u03b1-synuclein pathology and Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -dependent transcriptional dysregulation, positioning Parkinson\u2019s disease as a nanostructural channelopathy.\n                <\/jats:p>","DOI":"10.64898\/2026.05.01.719272","type":"posted-content","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T15:35:17Z","timestamp":1777995317000},"source":"Crossref","is-referenced-by-count":0,"title":["Nanoscale CaV channel reorganization links \u03b1-synuclein pathology to calcium-dependent transcriptional dysregulation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1491-3068","authenticated-orcid":false,"given":"Zolt\u00e1n J.","family":"Kov\u00e1cs","sequence":"first","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, 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