Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

Abstract

BACKGROUND: The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity-dependent; however, the detailed mechanisms underlying activity-dependent α-synuclein transmission in Parkinson's disease remain unclear. OBJECTIVE: To examine whether α-synuclein transmission is affected by Ca²⁺ -calmodulin-calcineurin signaling in cultured cells and mouse models of Parkinson's disease. METHODS: Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca²⁺ -calmodulin-calcineurin signaling on the neuronal uptake of α-synuclein preformed fibrils. The effects of modulating Ca²⁺ -calmodulin-calcineurin signaling on the development of α-synuclein pathology were examined using a mouse model injected with α-synuclein preformed fibrils. RESULTS: Modulation of Ca²⁺ -calmodulin-calcineurin signaling by inhibiting voltage-gated Ca²⁺ channels, calmodulin, and calcineurin blocked the neuronal uptake of α-synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage-gated Ca²⁺ channel differentially contributed to the neuronal uptake of α-synuclein preformed fibrils. In wild-type mice inoculated with α-synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α-synuclein pathology. CONCLUSION: Our data suggest that Ca²⁺ -calmodulin-calcineurin signaling modulates α-synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.