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Abnormal Gangliosides are Localized in Lipid Rafts in Sanfilippo (MPS3a) Mouse Brain

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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 (GM3) 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.

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Acknowledgments

Supported in part by USPHS Grant NS36866 to GD, the Children’s Brain Diseases Foundation for sabbatical support to GD and an NHMRC of Australia (grant no. 399355 to JJH, EJK and KMH). We would like to acknowledge the excellent technical assistance of Sylvia Dawson and S. Duplock.

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Authors and Affiliations

  1. University of Chicago, Chicago, IL, USA

    G. Dawson

  2. Lysosomal Diseases Research Unit, SA Pathology at the WCH, North Adelaide, SA, Australia

    M. Fuller, K. M. Helmsley & J. J. Hopwood

Authors
  1. G. Dawson
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  2. M. Fuller
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  3. K. M. Helmsley
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  4. J. J. Hopwood
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Correspondence to G. Dawson.

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Special Issue: In Honor of Bob Leeden.

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Dawson, G., Fuller, M., Helmsley, K.M. et al. Abnormal Gangliosides are Localized in Lipid Rafts in Sanfilippo (MPS3a) Mouse Brain. Neurochem Res 37, 1372–1380 (2012). https://doi.org/10.1007/s11064-012-0761-x

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  • DOI: https://doi.org/10.1007/s11064-012-0761-x

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