Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis

Sabrina Jabs, Arne Quitsch, Reijo Käkelä, Bettina Koch, Jaana Tyynelä, Helmut Brade, Markus Glatzel, Steven Walkley, Paul Saftig, Marie T. Vanier, Thomas Braulke

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.

Original languageEnglish (US)
Pages (from-to)1415-1425
Number of pages11
JournalJournal of Neurochemistry
Issue number3
StatePublished - Aug 2008


  • Bis(monoacylglycero)phosphate
  • Cathepsin D
  • GM2 ganglioside
  • Lysosomes
  • Mouse brain
  • Neuronal ceroid lipofuscinosis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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