Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin.
In cerebral adrenoleukodystrophy (cALD), an accumulation of very long chain fatty acids stems from a defect of the peroxisomal ALD protein (ALDP) and results in the loss of myelin/oligodendrocytes, induction of inflammatory disease and mental deterioration. In brain white matter of cALD patients, we observed not only increased levels of very long chain fatty acid but also reduced levels of plasmenylethanolamine (PlsEtn) and increased levels of reactive oxygen species (ROS). The loss of PlsEtn was greatest in the plaque area and lesser but significant at histologically normal-looking areas of the cALD brain. The reduction in PlsEtn was related to oxidative stress, as supported by increased levels of reactive lipid aldehydes (4-hydroxynonenal and acrolein) and deleterious oxidized proteins (protein carbonyl) in all areas of the cALD brain. This inverse relationship between the levels of PlsEtn and reactive oxygen species (ROS) was further supported in an in vitro study using gene-silencing for dihydroxyacetone phosphate-acyl transferase, a key enzyme for PlsEtn biosynthesis. Levels of PlsEtn were also found decreased in vitro following gene-silencing for the ALDP/ALD-related protein. Furthermore, low levels of PlsEtn were detected in brain white matter of ALDP knock out (KO) mice. A treatment of ALDP KO mice with lovastatin increased PlsEtn levels in the brain. Further, in an in vitro study, lovastatin treatment of rat C6 glial cells increased PlsEtn biosynthesis and reduced the cytokine-induced ROS accumulation. In summary, this study reports that altered metabolism of PlsEtn and ROS in cALD may be corrected by lovastatin treatment.
Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA. khanm@musc.edu
Mushfiquddin
M
Khan
Jaspreet
J
Singh
Inderjit
I
Singh
D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D054022:Cerebrum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002648:Child; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010955:Plasmalogens / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D010955:Plasmalogens; D017382:Reactive Oxygen Species; C020791:phosphatidal ethanolamines; D008148:Lovastatin