Kovacs, Z. J.; Dixon, R. E.; Dickson, E. J.

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 alpha-synuclein pre-formed fibrils trigger a reorganization of voltage-gated calcium (CaV) channels in cultured mouse cortical neurons, increasing their clustering at the soma and dendrites. We find that alpha-synuclein fibrils promote cyclin-dependent kinase 5-mediated phosphorylation of KV2.1 at serine 603, enhancing its scaffolding capacity for CaV channels. Disrupting CaV-KV2.1 coupling with a competitive peptide or pharmacological CDK5 inhibition restores channel proximity to control levels. Functionally, the enhanced CaV 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 CaV-KV2.1 interactions or inhibiting CaV channel activity. These findings identify nanoscale CaV channel remodeling as a mechanistic link between alpha-synuclein pathology and Ca2+-dependent transcriptional dysregulation, positioning Parkinson's disease as a nanostructural channelopathy.