Glycobiology Advance Access originally published online on January 12, 2005
Glycobiology 2005 15(6):637-648; doi:10.1093/glycob/cwi042
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Glycobiology vol. 15 no. 6 © Oxford University Press 2005; all rights reserved.
Characterization of lipid-linked oligosaccharide accumulation in mouse models of Batten disease
3 Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390; 4 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390; 5 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
1 These authors contributed equally to this work.
2 To whom correspondence should be addressed; e-mail: sandra.hofmann{at}utsouthwestern.edu
Received on November 2, 2004; revised on January 4, 2005; accepted on January 6, 2005
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 examine eight mouse models of lysosomal storage disorders by modern 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 knockoutmouse 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.
Key words: Batten disease / dolichol / lipofuscinosis / lysosome / storage disorders
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