Sphingolipids in the Pathogenesis of Parkinson's Disease and Parkinsonism

Trends Endocrinol Metab. 2019 Feb;30(2):106-117. doi: 10.1016/j.tem.2018.11.003. Epub 2018 Dec 6.


The pathogenic mechanisms underlying Parkinson's disease (PD)/parkinsonism affect mitochondrial and endolysosomal trafficking. The retromer is required to retrieve some proteins from endosomes to the Golgi and plasma membrane. Here, we discuss how retromer-dependent retrieval also affects ceramide metabolism. Compelling studies across PD models in Drosophila and mammalian neurons reveal a pathogenic cascade implicating retromer dysfunction and mitochondrial defects. We argue that ceramides may play a critical role in the pathobiology based on the studies of PLA2G6 and VPS35 in Drosophila mutants and human knock-down cells. In addition, pathogenic variants in many lysosomal storage disorder genes have recently been associated with PD, suggesting a potential overlap between the pathogenic mechanisms underlying these disorders. We propose that disruption of ceramide metabolism may affect endolysosomal and mitochondrial function, and plays an important role in PD/parkinsonism.

Keywords: PLA2G6; Vps35; desipramine; endolysosomal trafficking; lysosomal storage diseases; mitochondria; myriocin; retromer; synuclein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drosophila
  • Drosophila Proteins / metabolism
  • Humans
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology
  • Sphingolipids / metabolism*


  • Drosophila Proteins
  • Sphingolipids