α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity

Cell Rep. 2023 Oct 31;42(10):113244. doi: 10.1016/j.celrep.2023.113244. Epub 2023 Oct 14.

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.

Keywords: CP: Neuroscience; IP(3); PIP5K; calcium; membrane contact sites; neurodegeneration; phosphoinositide PI(4,5)P(2); α-Syn.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Neurons / metabolism
  • Parkinson Disease* / pathology
  • Phosphatidylinositol 4,5-Diphosphate* / metabolism
  • Phosphotransferases (Alcohol Group Acceptor)* / metabolism
  • Protein Aggregation, Pathological* / metabolism
  • Signal Transduction
  • alpha-Synuclein* / metabolism

Substances

  • alpha-Synuclein
  • Phosphatidylinositol 4,5-Diphosphate
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Phosphotransferases (Alcohol Group Acceptor)