TY - JOUR
T1 - X-linked adrenoleukodystrophy
T2 - ASHG 2004 Meeting Toronto
AU - Jia, Zhenzhen
AU - Pei, Zhengtong
AU - Li, Yuanyuan
AU - Wei, Liumei
AU - Smith, Kirby D.
AU - Watkins, Paul A.
N1 - Funding Information:
The authors thank Dr. Hugo Moser, Ann Moser, and the Neuroscience Core of Kennedy Krieger Institute’s Mental Retardation Developmental Disabilities Research Center for providing human skin fibroblasts from controls and patients with X-ALD. Thanks also to Dr. Moser for thoughful discussions of the data. We thank Dr. Gerald Hart (Johns Hopkins University School of Medicine) for Neuro2a cells and Dr. Ahamed Hossain (Kennedy Krieger Institute) for GAPDH plasmid DNA. This work was supported by NIH Grants NS37355, HD10981, and HD24061.
PY - 2004/9
Y1 - 2004/9
N2 - The principal biochemical abnormality in the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is elevated plasma and tissue levels of very long-chain fatty acids (VLCFA). Enzymes with very long-chain acyl-CoA synthetase (VLACS) activity are required for VLCFA metabolism, including degradation by peroxisomal β-oxidation or incorporation into complex lipids, and may also participate in VLCFA synthesis. Two enzymes with VLACS activity, ACSVL1 and BG1, were investigated for their potential role in X-ALD biochemical pathology. Skin fibroblast mRNA levels for ACSVL1, an enzyme previously shown to be in peroxisomes and to participate in VLCFA β-oxidation, were not significantly different between normal controls, patients with childhood cerebral X-ALD, and patients with adrenomyeloneuropathy. Similar results were obtained with mRNA for BG1, a non-peroxisomal enzyme that is highly expressed in nervous system, adrenal gland, and testis, the principal tissues pathologically affected in X-ALD. No significant differences in the immunohistochemical staining patterns of tissues expressing either ACSVL1 or BG1 were observed when wild-type and X-ALD mice were compared. Western blot analysis of BG1 protein levels showed no differences between fibroblasts from controls, cerebral X-ALD, or adrenomyeloneuropathy patients. BG1 protein levels were similar in wild-type and X-ALD mouse brain, spinal cord, testis, and adrenal gland. We hypothesized that one function of BG1 was to direct VLCFA into the cholesterol ester synthesis pathway. However, BG1 depletion in Neuro2a cells using RNA interference did not decrease incorporation of labeled VLCFA into cholesterol esters. We conclude that the role, if any, of ACSVL1 and BG1 in X-ALD biochemical pathology is indirect.
AB - The principal biochemical abnormality in the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is elevated plasma and tissue levels of very long-chain fatty acids (VLCFA). Enzymes with very long-chain acyl-CoA synthetase (VLACS) activity are required for VLCFA metabolism, including degradation by peroxisomal β-oxidation or incorporation into complex lipids, and may also participate in VLCFA synthesis. Two enzymes with VLACS activity, ACSVL1 and BG1, were investigated for their potential role in X-ALD biochemical pathology. Skin fibroblast mRNA levels for ACSVL1, an enzyme previously shown to be in peroxisomes and to participate in VLCFA β-oxidation, were not significantly different between normal controls, patients with childhood cerebral X-ALD, and patients with adrenomyeloneuropathy. Similar results were obtained with mRNA for BG1, a non-peroxisomal enzyme that is highly expressed in nervous system, adrenal gland, and testis, the principal tissues pathologically affected in X-ALD. No significant differences in the immunohistochemical staining patterns of tissues expressing either ACSVL1 or BG1 were observed when wild-type and X-ALD mice were compared. Western blot analysis of BG1 protein levels showed no differences between fibroblasts from controls, cerebral X-ALD, or adrenomyeloneuropathy patients. BG1 protein levels were similar in wild-type and X-ALD mouse brain, spinal cord, testis, and adrenal gland. We hypothesized that one function of BG1 was to direct VLCFA into the cholesterol ester synthesis pathway. However, BG1 depletion in Neuro2a cells using RNA interference did not decrease incorporation of labeled VLCFA into cholesterol esters. We conclude that the role, if any, of ACSVL1 and BG1 in X-ALD biochemical pathology is indirect.
KW - Bubblegum
KW - Fatty acid activation
KW - Fatty acid metabolism
KW - Fatty acid transport protein
KW - Mouse models
KW - Neurodegenerative diseases
KW - Peroxisome
KW - Very long-chain acyl-CoA synthetase
KW - X-linked adrenoleukodystrophy
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UR - http://www.scopus.com/inward/citedby.url?scp=4744359221&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2004.06.015
DO - 10.1016/j.ymgme.2004.06.015
M3 - Conference article
C2 - 15464426
AN - SCOPUS:4744359221
SN - 1096-7192
VL - 83
SP - 117
EP - 127
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
Y2 - 26 October 2004 through 26 October 2004
ER -