title: Phospholipase D activity is altered in X-linked adrenoleukodystrophy heterozygous carriers, but not in hemizygous patients.
abstract: Abnormalities in levels of choline and its metabolites have been reported in the lesions of brains of X-linked adrenoleukodystrophy (X-ALD) patients. We have examined the turnover of the major choline-containing phospholipid, phosphatidylcholine (PtdCho), in fibroblasts from hemizygous X-ALD, heterozygous X-ALD, Zellweger syndrome (ZW), and male and female control individuals to assess possible alterations in PtdCho metabolism mediated by activation of protein kinase C (PKC). Hydrolysis of PtdCho by phospholipase D (PLD) and resynthesis of PtdCho from labeled choline were stimulated 2- to 4-fold by PKC activation with the phorbol ester, 4beta-12-O-tetradecanoylphorbol-13-acetate (beta-TPA), in all cells except those from heterozygous X-ALD individuals. No differences in quantity or intracellular distribution of PKC activity, PKC isoforms by Western blot analysis, or of the PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), were apparent in any of the cells. Thus, altered PtdCho metabolism was not directly linked to either of these inherited defects that result in abnormal peroxisomal functions. Further, altered responsiveness of PLD in X-ALD heterozygotes was independent of changes in PKC and MARCKS.
authors.affiliation: Department of Pediatrics, Atlantic Research Centre, Dalhousie University, 5849 University Avenue, Halifax, NS B3H 4H7, Canada.
authors.forename: H E
authors.initials: HE
authors.lastname: Logan
authors.forename: D M
authors.initials: DM
authors.lastname: Byers
authors.forename: N D
authors.initials: ND
authors.lastname: Ridgway
authors.forename: H W
authors.initials: HW
authors.lastname: Cook
mesh_terms: D002353:Carrier State; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D008040:Genetic Linkage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008565:Membrane Proteins; D009006:Monosomy; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D019301:Oleic Acid / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000201:enzymology*; D010713:Phosphatidylcholines / Q000378:metabolism; D010739:Phospholipase D / Q000032:analysis*; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D012729:Sex Chromosome Aberrations / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014960:X Chromosome; D015211:Zellweger Syndrome / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D019301:Oleic Acid; D011493:Protein Kinase C; D010739:Phospholipase D; D002794:Choline; D013755:Tetradecanoylphorbol Acetate