α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.
Cell Rep
; 42(10): 113244, 2023 10 31.
Article
in En
| MEDLINE
| ID: mdl-37838947
ABSTRACT
Anomalous aggregation of α-synuclein (α-Syn) is a pathological hallmark of many degenerative synucleinopathies including Lewy body dementia (LBD) and Parkinson's disease (PD). Despite its strong link to disease, the precise molecular mechanisms that link α-Syn aggregation to neurodegeneration have yet to be elucidated. Here, we find that elevated α-Syn leads to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P2, which precipitates α-Syn aggregation and drives toxic increases in mitochondrial Ca2+ and reactive oxygen species leading to neuronal death. Upstream of this toxic signaling pathway is PIP5K1γ, whose abundance and localization is enhanced at the PM by α-Syn-dependent increases in ARF6. Selective inhibition of PIP5K1γ or knockout of ARF6 in neurons rescues α-Syn aggregation and cellular phenotypes of toxicity. Collectively, our data suggest that modulation of phosphoinositide metabolism may be a therapeutic target to slow neurodegeneration for PD and other related neurodegenerative disorders.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Phosphotransferases (Alcohol Group Acceptor)
/
Phosphatidylinositol 4,5-Diphosphate
/
Alpha-Synuclein
/
Protein Aggregation, Pathological
Limits:
Humans
Language:
En
Journal:
Cell Rep
Year:
2023
Document type:
Article
Affiliation country:
United States