Phosphatidylinositol 3-phosphate metabolism impacts cellular a-synuclein localization in Saccharomyces cerevisiae
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Abstract
Alpha-synuclein (αSyn), a hallmark protein of synucleino pathies such as Parkinson’s disease (PD), is likely to be
involved in neuronal membrane trafficking and synaptic
vesicle dynamics at axon terminals. Its specific binding to
anionic phospholipids, such as phosphatidylinositol phos phates that are essential for intracellular signaling and mem brane trafficking, suggests an involvement in vesicular
transport processes. In Saccharomyces cerevisiae, a model or ganism for cell biological PD research, human αSyn localizes
to the plasma membrane via the secretory machinery.
Employing this yeast model, we investigated the impact of
αSyn on cellular quality control mechanisms. Additionally, we
focused on the effect of αSyn expression in yeast mutants
impaired in specific phospholipid biosynthesis and transport
pathways, including endovacuolar trafficking and autophagy.
In the deletion strains vps34Δ and vps15Δ, lacking phospha tidylinositol 3-phosphate (PI3P) biosynthesis, αSyn mis localizes in the cytosol, and significantly reduces cell viability.
In these strains, αSyn species containing an intact lipid binding N terminus also form large perivacuolar, lipid-rich
accumulations. In wild type cells, αSyn expression alters the
morphology of PI3P-rich membrane structures and upregu lates transcription of SEC4, which encodes a key regulator of
the late secretory pathway. Moreover, αSyn colocalizes with
overexpressed Sec4 at the emerging cell bud. Our findings
demonstrate that PI3P is critical for the targeting of αSyn to
the yeast plasma membrane via the secretory pathway,
revealing a potential entry point into this complex machinery.
Understanding the relationship between αSyn and vesicular
trafficking in this system will enhance our knowledge of αSyn trafficking in mammalian cells and, eventually, in PD, offering
new research avenues.
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The journal of biological chemistry, 301, 10, Elsevier B.V., Amsterdam, 2025, https://doi.org/10.1016/j.jbc.2025.110666