Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain

Cell Metab. 2018 Oct 2;28(4):605-618.e6. doi: 10.1016/j.cmet.2018.05.019. Epub 2018 Jun 14.


Mutations in PLA2G6 (PARK14) cause neurodegenerative disorders in humans, including autosomal recessive neuroaxonal dystrophy and early-onset parkinsonism. We show that loss of iPLA2-VIA, the fly homolog of PLA2G6, reduces lifespan, impairs synaptic transmission, and causes neurodegeneration. Phospholipases typically hydrolyze glycerol phospholipids, but loss of iPLA2-VIA does not affect the phospholipid composition of brain tissue but rather causes an elevation in ceramides. Reducing ceramides with drugs, including myriocin or desipramine, alleviates lysosomal stress and suppresses neurodegeneration. iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling. Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide. This induces a positive feedback loop that affects membrane fluidity and impairs retromer function and neuronal function. Similar defects are observed upon loss of vps26 or vps35 or overexpression of α-synuclein, indicating that these defects may be common in Parkinson disease.

Keywords: Parkinson disease; ceramide phosphatidylethanolamine; complex I; endosome; infantile neuroaxonal dystrophy (INAD); lysosomal storage disease; lysosome; mitochondria; neurodegeneration with brain iron accumulation; shingomyelin.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Line, Tumor
  • Ceramides / metabolism*
  • Drosophila / genetics
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Feedback, Physiological
  • Female
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism*
  • Group X Phospholipases A2 / metabolism*
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Male
  • Membrane Fluidity
  • Mutation
  • Neurons / metabolism
  • Nuclear Proteins / chemistry
  • Parkinson Disease / metabolism*
  • RNA-Binding Proteins / chemistry
  • Sphingolipids / metabolism
  • Vesicular Transport Proteins / metabolism*
  • alpha-Synuclein / metabolism*


  • Ceramides
  • Drosophila Proteins
  • Nuclear Proteins
  • PSI protein, Drosophila
  • RNA-Binding Proteins
  • Sphingolipids
  • VPS26A protein, human
  • VPS35 protein, human
  • Vesicular Transport Proteins
  • Vps26 protein, Drosophila
  • Vps35 protein, Drosophila
  • alpha-Synuclein
  • Group VI Phospholipases A2
  • Group X Phospholipases A2
  • PLA2G6 protein, human
  • iPLA2-VIA protein, Drosophila