Ca2+-Calmodulin-Calcineurin Signaling Modulates alpha-Synuclein Transmission

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 alpha-synuclein transmission in Parkinson's disease remain unclear. Objective: To examine whether alpha-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 alpha-synuclein preformed fibrils. The effects of modulating Ca2+-calmodulin-calcineurin signaling on the development of alpha-synuclein pathology were examined using a mouse model injected with alpha-synuclein preformed fibrils. Results: Modulation of Ca2+-calmodulin-calcineurin signaling by inhibiting voltage-gated Ca2+ channels, calmodulin, and calcineurin blocked the neuronal uptake of alpha-synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage-gated Ca2+ channel differentially contributed to the neuronal uptake of alpha-synuclein preformed fibrils. In wild-type mice inoculated with alpha-synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of alpha-synuclein pathology. Conclusion: Our data suggest that Ca2+-calmodulin-calcineurin signaling modulates alpha-synuclein transmission and has potential as a therapeutic target for Parkinson's disease. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.