| First Author | Horvath JD | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 10 | Pages | 113244 |
| PubMed ID | 37838947 | Mgi Jnum | J:342054 |
| Mgi Id | MGI:7544789 | Doi | 10.1016/j.celrep.2023.113244 |
| Citation | Horvath JD, et al. (2023) alpha-Synuclein-dependent increases in PIP5K1gamma drive inositol signaling to promote neurotoxicity. Cell Rep 42(10):113244 |
| abstractText | Anomalous aggregation of alpha-synuclein (alpha-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 alpha-Syn aggregation to neurodegeneration have yet to be elucidated. Here, we find that elevated alpha-Syn leads to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P(2), which precipitates alpha-Syn aggregation and drives toxic increases in mitochondrial Ca(2+) and reactive oxygen species leading to neuronal death. Upstream of this toxic signaling pathway is PIP5K1gamma, whose abundance and localization is enhanced at the PM by alpha-Syn-dependent increases in ARF6. Selective inhibition of PIP5K1gamma or knockout of ARF6 in neurons rescues alpha-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. |
