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.

Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein

“…Our group also explored the mechanisms underlying α-synuclein transmission. Following establishment of a mouse model demonstrating the extensive spread of α-synuclein pathology from the olfactory bulb by injection of α-synuclein PFF (Uemura et al 2021 ), we showed that inhibition of the Ca2+-calmodulin-calcineurin signaling blocked the neuronal uptake of α-synuclein preformed fibrils via macropinocytosis (Ueda et al 2023 ). Thus Ca2+-calmodulin-calcineurin signaling can be a potential therapeutic target for PD.…”