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Trends Endocrinol Metab. 2018 Dec 6. pii: S1043-2760(18)30203-0. doi: 10.1016/j.tem.2018.11.003. [Epub ahead of print]

Sphingolipids in the Pathogenesis of Parkinson's Disease and Parkinsonism.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
2
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.

Abstract

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

PMID:
30528460
DOI:
10.1016/j.tem.2018.11.003

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