Journal
TRENDS IN ENDOCRINOLOGY AND METABOLISM
Volume 30, Issue 2, Pages 106-117Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tem.2018.11.003
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Funding
- Parkinson Canada
- Stand by Eli Foundation
- Friedreich's Ataxia Research Alliance
- CureFA Foundation
- Target ALS
- Huffington Foundation
- Robert A. and Renee E. Belfer Family Foundation
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The pathogenic mechanisms underlying Parkinson's disease (PD)/parkinsonism affect mitochondria' 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 mitochondria' function, and plays an important role in PD/parkinsonism.
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