Multi-system disorders of glycosphingolipid and ganglioside metabolism
- Division of Human Genetics, Cincinnati Childrenrsquos Hospital Medical Center and the Departments of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039
- 1To whom correspondence should be addressed. e-mail: greg.grabowski{at}cchmc.org
-
↵2 Y-H. Xu, S. Barnes, and Y. Sun contributed equally to this work.
Abstract
Glycosphingolipids (GSLs) and gangliosides are a group of bioactive glycolipids that include cerebrosides, globosides, and gangliosides. These lipids play major roles in signal transduction, cell adhesion, modulating growth factor/hormone receptor, antigen recognition, and protein trafficking. Specific genetic defects in lysosomal hydrolases disrupt normal GSL and ganglioside metabolism leading to their excess accumulation in cellular compartments, particularly in the lysosome, i.e., lysosomal storage diseases (LSDs). The storage diseases of GSLs and gangliosides affect all organ systems, but the central nervous system (CNS) is primarily involved in many. Current treatments can attenuate the visceral disease, but the management of CNS involvement remains an unmet medical need. Early interventions that alter the CNS disease have shown promise in delaying neurologic involvement in several CNS LSDs. Consequently, effective treatment for such devastating inherited diseases requires an understanding of the early developmental and pathological mechanisms of GSL and ganglioside flux (synthesis and degradation) that underlie the CNS diseases. These are the focus of this review.
Footnotes
-
- Abbreviations:
- AC
- acid ceramidase
- ASA
- arylsulfatase A
- aSMase
- acid sphingomyelinase
- BDNF
- brain-derived neurotrophic factor
- CBE
- conduritol B epoxide
- CERT
- ceramide transfer protein
- CGT
- ceramide UDP-galactosyltransferase
- CNS
- central nervous system
- EET
- enzyme enhancement therapy
- ER
- endoplasmic reticulum
- ERK
- extracellular signal-regulated kinase
- FAPP2
- four-phosphate adaptor protein 2
- GALC
- galactosylceramide-β-galactosidase
- Gb3
- globotrioaosylshyceramide
- GCase
- acidβ-glucosidase or glucocerebrosidase
- GCS
- glucosylceramide synthase
- GD3 synthase
- α-N-acetyl-neuraminide α-2,8-sialyltransferase
- GM3 synthase
- LacCer α-2,3-sialyltransferase
- GSL
- glycosphingolipids
- Hex A
- β-hexosaminidase A
- Hex B
- β-hexosaminidase B
- IL
- interleukin
- iNKT
- invariant natural killer T
- LacCer
- lactosylceramide
- LacSph
- lactosylsphingosine
- LSD
- lysosomal storage disease
- LTP
- long-term potentiation
- lyso-Gb3
- globotriaosylsphingosine
- MLD
- metachromatic leukodystrophy
- NB-DGJ
- N-butyldeoxygalactonojirimycin
- NB-DNJ
- N-butyl-deoxynojirimycin
- NGF
- nerve growth factor
- NPA/B
- Niemann-Pick disease Types A and B
- nSMase
- Neutral sphingomyelinase
- Pgp
- P-glycoprotein
- PNS
- peripheral nervous system
- Sap
- saposin
- SPT
- serine-palmitoyltransferase
- SSIT
- substrate synthesis inhibition therapy
- TNFα
- tumor necrosis factor-α
- UPR
- unfolded protein response
-
This work was supported by National Institutes of Health grants to G.A.G. (NS64352, HD59823, and DK36729). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
- Received November 13, 2009.
- Revision received March 8, 2010.
- Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.
