Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain.

Abstract

Allogenic stem cell transplantation can reduce lysosomal storage of heparan sulfate-derived oligosaccharides by up to 27 % in Sanfilippo MPS3a brain, but does not reduce the abnormal storage of sialolactosylceramide (G(M3)) or improve neurological symptoms, suggesting that ganglioside storage is in a non-lysosomal compartment. To investigate this further we isolated the Triton X100-insoluble at 4 °C, lipid raft (LR) fraction from a sucrose-density gradient from cerebral hemispheres of a 7 month old mouse model of Sanfilippo MPS3a and age-matched control mouse brain. HPLC/MS/MS analysis revealed the expected enrichment of normal complex gangliosides, ceramides, galatosylceramides and sphingomyelin enrichment in this LR fraction. The abnormal HS-derived oligosaccharide storage material was in the Triton X100-soluble at 4 °C fractions (8-12),whereas both GM3 and sialo[GalNAc]lactosylceramide (GM2) were found exclusively in the LR fraction (fractions 3 and 4) and were >90 % C18:0 fatty acid, suggesting a neuronal origin. Further analysis also revealed a >threefold increase in the late-endosome marker bis (monoacylglycerol) phosphate (>70 % as C22:6/22:6-BMP) in non-LR fractions 8-12 whereas different forms of the proposed BMP precursor, phosphatidylglycerol (PG) were in both LR and non-LR fractions and were less elevated in MPS3a brain. Thus heparan sulfate-derived oligosaccharide storage is associated with abnormal lipid accumulation in both lysosomal (BMP) and non-lysosomal (GM3 and GM2) compartments.

• Authors: G Dawson, M Fuller, K M Helmsley, J J Hopwood
• Journal: Neurochemical research (Neurochem Res) Vol. 37 Issue 6 Pg. 1372-80 (Jun 2012) ISSN: 1573-6903 [Electronic] United States
• PMID: 22484966 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• G(M3) Ganglioside
• Gangliosides
• Lysophospholipids
• Monoglycerides
• bis(monoacylglyceryl)phosphate
• G(M2) Ganglioside

Topics

• Animals
• Brain (metabolism)
• G(M2) Ganglioside (metabolism)
• G(M3) Ganglioside (metabolism)
• Gangliosides (metabolism)
• Lysophospholipids (metabolism)
• Lysosomes (metabolism)
• Membrane Microdomains (metabolism)
• Mice
• Monoglycerides (metabolism)
• Mucopolysaccharidosis III (metabolism)
• Tandem Mass Spectrometry