Glycobiology Advance Access published online on January 12, 2005
Glycobiology, doi:10.1093/glycob/cwi042
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1 Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 'The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors; The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
* To whom correspondence should be addressed. The neuronal ceroid lipofuscinoses (NCLs, also known collectively as Batten disease) are a group of lysosomal storage disorders characterized by the accumulation of autofluorescent storage material in the brain and other tissues. A number of genes underlying various forms of NCL have been cloned, but the basis for the neurodegeneration in any of these is unknown. High levels of dolichol pyrophosphoryl oligosaccharides have previously been demonstrated in brain tissue from several NCL patients but the specificity of the effect for the NCLs has been unclear. In the present study, we have examined eight mouse models of lysosomal storage disorders by modern fluorophore assisted carbohydrate electrophoresis (FACE) and found striking lipid-linked oligosaccharide (LLO) accumulation in NCL mouse models (especially CLN1, CLN6 and CLN8 knockout or mutant mice), but not in several other lysosomal storage disorders affecting the brain. Using a mouse model of the most severe form of NCL (the PPT1 knockout mouse), we show that accumulated LLOs are not the result of a defect in LLO synthesis, extension or transfer but rather are catabolic intermediates derived from LLO degradation. LLOs are enriched about 60-fold in the autofluorescent storage material purified from PPT1 knockout mouse brain, but comprise only 0.3% of the autofluorescent storage material by mass. The accumulation of LLOs is postulated to result from inhibition of late stages of lysosomal degradation of autophagosomes, which may be enriched in these metabolic precursors.
Received November 2, 2004
Revised January 4, 2005
Accepted January 5, 2005
Article
Characterization of lipid-linked oligosaccharide accumulation in mouse models of Batten disease
2 Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 'The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
3 Center for Aging and Developmental Biology, Department of Biochemistry and Biophysics and Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
4 Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
5 Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Sandra L. Hofmann, E-mail: sandra.hofmann{at}utsouthwestern.edu
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