title: Targeted metabolomic analyses of cellular models of pelizaeus-merzbacher disease reveal plasmalogen and myo-inositol solute carrier dysfunction.
abstract: BACKGROUND
  Leukodystrophies are devastating diseases characterized by dys- and hypo-myelination. While there are a number of histological and imaging studies of these disorders, there are limited biochemical data available. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models.
  
  
  RESULTS
  In both PMD fibroblasts and lymphocytes, and 158JP oligodendrocytes, ethanolamine plasmalogens were significantly decreased. Labeling studies with 158JP oligodendrocytes further demonstrated a decreased rate of lipid remodeling at sn-2. Targeted metabolomics analyses of these cells revealed dramatic increases in cellular levels of myo-inositol. Further uptake studies demonstrated increased rates of myo-inositol uptake by PMD lymphocytes.
  
  
  CONCLUSIONS
  Our data demonstrating PlsEtn decrements, support previous studies indicating leukodystrophy cells possess significant peroxisomal deficits. Our data for the first time also demonstrate that decrements in peroxisomal function coupled with the PLP1 gene defects of PMD, result in changes in the function of membrane myo-inositol solute carriers resulting in dramatic increases in cellular myo-inositol levels.
authors.affiliation: Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK S7N4L8, Canada. p.wood@phenomenome.com
authors.forename: Paul L
authors.initials: PL
authors.lastname: Wood
authors.forename: Tara
authors.initials: T
authors.lastname: Smith
authors.forename: Lindsay
authors.initials: L
authors.lastname: Pelzer
authors.forename: Dayan B
authors.initials: DB
authors.lastname: Goodenowe
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009836:Oligodendroglia / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000378:metabolism*; D010955:Plasmalogens / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D010955:Plasmalogens; D027981:Symporters; C020791:phosphatidal ethanolamines; C073884:SLC5A3 protein, human; D007294:Inositol