Sphingolipids in the Pathogenesis of Parkinson’s Disease and Parkinsonism

• Published in: Trends in endocrinology and metabolism 2019-02, Vol.30 (2), p.106-117
• Main Authors: Lin, Guang, Wang, Liping, Marcogliese, Paul C., Bellen, Hugo J.
• Format: Article
• Language: English
• Subjects: Animals; desipramine; Drosophila; Drosophila Proteins - metabolism; endolysosomal trafficking; Humans; lysosomal storage diseases; mitochondria; myriocin; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; PLA2G6; retromer; Sphingolipids - metabolism; synuclein; Vps35
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2018.11.003

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. Studies in the past two decades suggest that both mitochondrial and endolysosomal trafficking pathways are affected in PD/parkinsonism. A pathogenic cascade of retromer dysfunction and endolysosomal defects leads to ceramide accumulation. GBA, an LSD gene, is the most common PD risk factor. Additionally, many other LSD genes have recently been associated with PD, indicating a potential overlap in PD and LSD pathogenesis. Disruptions in the sphingolipid metabolism pathway may connect a variety of phenotypes including both mitochondrial and endolysosomal defects, and may play a prominent role in PD/parkinsonism.