title: Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8mnd : implications to delayed myelination and oligodendrocyte maturation.
abstract: OBJECTIVE
  CLN8 deficiency underlies one of a group of devastating childhood neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The function of the CLN8 protein is currently unknown, but a role in lipid metabolism has been proposed. In human CLN8 diseased brains, alterations in lipid composition have been detected. To further investigate the connection of CLN8 to lipid metabolism, we characterized the lipid composition of early symptomatic Cln8-deficient mouse (Cln8(mnd)) brains.
  
  
  METHODS
  For lipid profiling, Cln8(mnd) cerebral cortical tissue was analysed by liquid chromatography/mass spectrometry. Galactolipid synthesis was measured through enzyme activity and real-time mRNA expression analyses. Based on the findings, myelination and white matter integrity were studied by immunohistochemistry, stereological methods, electron microscopy and magnetic resonance imaging. The development of myelin-forming oligodendrocytes was also studied in vitro.
  
  
  RESULTS
  Sphingolipid profiling showed a selective reduction in myelin-enriched galactolipids. The mRNA expression and activity of UDP-galactose:ceramide galactosyltransferase (CGT), the key enzyme in the galactolipid synthesis, was reduced in the Cln8(mnd) brain. Expression of oligodendrocyte markers suggests a maturation defect. The amount of myelin was reduced in 1-month-old Cln8(mnd) mice, but reached normal levels by 5 months of age. The level of Cln8 gene expression followed the developmental pattern of myelin formation and was high in primary oligodendrocytes.
  
  
  CONCLUSIONS
  Taken together, these observations suggest that galactolipid deficiency and delayed myelin maturation characterize the early CLN8 disease pathogenesis through a maturation defect of oligodendrocytes.
authors: Folkhälsan Institute of Genetics, Helsinki, Finland. mervi.kuronen@helsinki.fi
authors: M
authors: M
authors: Kuronen
authors: M
authors: M
authors: Hermansson
authors: O
authors: O
authors: Manninen
authors: I
authors: I
authors: Zech
authors: M
authors: M
authors: Talvitie
authors: T
authors: T
authors: Laitinen
authors: O
authors: O
authors: Gröhn
authors: P
authors: P
authors: Somerharju
authors: M
authors: M
authors: Eckhardt
authors: J D
authors: JD
authors: Cooper
authors: A-E
authors: AE
authors: Lehesjoki
authors: U
authors: U
authors: Lahtinen
authors: O
authors: O
authors: Kopra
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors
chemical_list: C498493:Cln8 protein, mouse; D008565:Membrane Proteins