Ca2+ -Calmodulin-Calcineurin Signaling Modulates α-Synuclein Transmission.
Mov Disord
; 38(6): 1056-1067, 2023 06.
Article
in En
| MEDLINE
| ID: mdl-37066491
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Synucleinopathies
Limits:
Animals
/
Humans
Language:
En
Journal:
Mov Disord
Journal subject:
NEUROLOGIA
Year:
2023
Document type:
Article
Affiliation country:
Japón