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

Mov Disord. 2023 Jun;38(6):1056-1067. doi: 10.1002/mds.29401. Epub 2023 Apr 17.


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.

Keywords: Ca2+-calmodulin-calcineurin signaling; Parkinson's disease; micropinocytosis; propagation; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Calmodulin / metabolism
  • Humans
  • Mice
  • Neurons / metabolism
  • Parkinson Disease* / pathology
  • Synucleinopathies*
  • alpha-Synuclein / metabolism


  • alpha-Synuclein
  • Calmodulin
  • Calcineurin