PHOSPHOLIPASE-D ACTIVITY IS ALTERED IN X-LINKED ADRENOLEUKODYSTROPHY HETEROZYGOUS CARRIERS, BUT NOT IN HEMIZYGOTIC PATIENTS

Abnormalities in levels of choline and its metabolites have been repor ted in the lesions of brains of X-linked adrenoleukodystrophy (X-ALD) patients. We have examined the turnover of the major choline-containin g phospholipid, phosphatidylcholine (PtdCho), in fibroblasts from hemi zygous X-ALD, heterozygous X-ALD, Zellweger syndrome (ZW), and male an d female control individuals to assess possible alterations in PtdCho metabolism mediated by activation of protein kinase C (PKC). Hydrolysi s of PtdCho by phospholipase D (PLD) and resynthesis of PtdCho from la beled choline were stimulated 2- to 4-fold by PKC activation with the phorbol ester, 4 beta-12-O-tetradecanoylphorbol-13-acetate (P-TPA), in all cells except those from heterozygous X-ALD individuals. No differ ences in quantity or intracellular distribution of PKC activity, PKC i soforms by Western blot analysis, or of the PKC substrate, myristoylat ed alanine-rich C kinase substrate (MARCKS), were apparent in any of t he cells. Thus, altered PtdCho metabolism was not directly linked to e ither of these inherited defects that result in abnormal peroxisomal f unctions. Further: altered responsiveness of PLD in X-ALD heterozygote s was independent of changes in PKC and MARCKS. (C) 1998 Elsevier Scie nce B.V. All rights reserved.