title: Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis.
abstract: 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.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Children's Hospital-Biochemistry, Hamburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jabs
authors.forename: Arne
authors.initials: A
authors.lastname: Quitsch
authors.forename: Reijo
authors.initials: R
authors.lastname: Käkelä
authors.forename: Bettina
authors.initials: B
authors.lastname: Koch
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.forename: Helmut
authors.initials: H
authors.lastname: Brade
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Steven
authors.initials: S
authors.lastname: Walkley
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005732:Gangliosides / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D007425:Intracellular Membranes / Q000737:chemistry / Q000473:pathology; D008055:Lipids / Q000096:biosynthesis / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050178:Monoglycerides / Q000378:metabolism* / Q000502:physiology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000473:pathology
chemical_list: D005732:Gangliosides; D008055:Lipids; D008246:Lysophospholipids; D050178:Monoglycerides; C012786:bis(monoacylglyceryl)phosphate; D002402:Cathepsin D