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

Disrupted calcium (Ca²⁺) homeostasis is a hallmark of neurodegenerative diseases, yet the mechanisms driving excessive Ca²⁺ 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_V2.1 at serine 603, enhancing its scaffolding capacity for Ca_V channels. Disrupting Ca_V-K_V2.1 coupling with a competitive peptide or pharmacological CDK5 inhibition restores channel proximity to control levels. Functionally, the enhanced Ca_V clustering amplifies depolarization-evoked Ca²⁺ 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_V2.1 interactions or inhibiting Ca_V channel activity. These findings identify nanoscale Ca_V channel remodeling as a mechanistic link between α-synuclein pathology and Ca²⁺-dependent transcriptional dysregulation, positioning Parkinson's disease as a nanostructural channelopathy.