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bioRxiv · 10.64898/2026.05.01.719272

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

Kovacs, Z. J.·Dixon, R. E.·Dickson, E. J.
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Abstract

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 -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 -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 -synuclein pathology and Ca2+-dependent transcriptional dysregulation, positioning Parkinsons disease as a nanostructural channelopathy.

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Kovacs, Z. J., Dixon, R. E., Dickson, E. J.. 2026-05-05. Nanoscale CaV channel reorganization links alpha-synuclein pathology to calcium-dependent transcriptional dysregulation. https://doi.org/10.64898/2026.05.01.719272

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