Nanoscale CaV channel reorganization links α-synuclein pathology to calcium-dependent transcriptional dysregulation

Abstract Disrupted calcium (Ca 2+ ) homeostasis is a hallmark of neurodegenerative diseases, yet the mechanisms driving excessive Ca 2+ entry at the neuronal plasma membrane remain poorly understood. Here, we show that α-synuclein pre-formed fibrils trigger a reorganization of voltage-gated calcium (Ca V ) channels in cultured mouse cortical neurons, increasing their clustering at the soma and dendrites. We find that α-synuclein fibrils promote cyclin-dependent kinase 5–mediated phosphorylation of K V 2.1 at serine 603, enhancing its scaffolding capacity for Ca V channels. Disrupting Ca V –K V 2.1 coupling with a competitive peptide or pharmacological CDK5 inhibition restores channel proximity to control levels. Functionally, the enhanced Ca V clustering amplifies depolarization-evoked Ca 2+ influx and drives aberrant excitation–transcription coupling, as reflected by elevated expression of the immediate early gene c-Fos. All effects were rescued by disrupting Ca V –K V 2.1 interactions or inhibiting Ca V channel activity. These findings identify nanoscale Ca V channel remodeling as a mechanistic link between α-synuclein pathology and Ca 2+ -dependent transcriptional dysregulation, positioning Parkinson’s disease as a nanostructural channelopathy.