Ca<sup>2+</sup>–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission
Jun Ueda, Norihito Uemura, Tomoyuki Ishimoto, Tomoyuki Taguchi, Masanori Sawamura, Etsuro Nakanishi, Masashi Ikuno, Shu‐ichi Matsuzawa, Hodaka Yamakado, Ryōsuke Takahashi
Abstract
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 Ca 2+ –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 Ca 2+ –calmodulin–calcineurin signaling on the neuronal uptake of α‐synuclein preformed fibrils. The effects of modulating Ca 2+ –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 Ca 2+ –calmodulin–calcineurin signaling by inhibiting voltage‐gated Ca 2+ channels, calmodulin, and calcineurin blocked the neuronal uptake of α‐synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage‐gated Ca 2+ 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 Ca 2+ –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.