Adrenoleukodystrophy (X-ALD) is a X-linked peroxisomal disorder which leads to neurological degeneration and is characterized by pathognomonic accumulation of saturated very long chain (SVLC) fatty acids (>C22) at peaks of C24:0 to C26:0. The normal oxidation of lignoceroyl-CoA as compared to deficient oxidation of lignoceric acid and deficient activity of lignoceroyl-CoA ligase in X-ALD peroxisomes and normalization of lignoceric acid oxidation by supplementation of X-ALD peroxisomes with lignoceroyl-CoA ligase clearly demonstrates that this pathognomonic accumulation of VLC fatty acids in X-ALD is due to impaired activity of peroxisomal VLC (Lignoceric acid) acylCoA ligase. The objectives of this proposal are to further understand the molecular basis of the abnormality in the peroxisomal metabolism of VLC fatty acids and the mechanism of demyelination in X-ALD. Achievement of these goals will be facilitated by the isolation of a c-DNA corresponding to the peroxisomal lignoceroyl-CoA ligase gene, chromosomal localization of the gene for lignoceroyl-CoA ligase and sequence analysis of cDNA from control and X-ALD tissues. Antibodies will be used to study levels of lignoceroyl-CoA ligase in X-ALD tissues and c-DNA will be used to measure the level of m-RNA in X-ALD tissues. The assembly of protein and lipid constituents into membranes with proper orientation for normal function in the cell is a subject of great interest. Studies concerning the topographical localization and transport of unsaturated (nervonic acid) and alpha-hydroxylated (alpha-hydroxylignoceric and alpha-hydroxynervonic acids) fatty acids as compared to lignoceric acid will provide information regarding the metabolic pathways of VLC fatty acids. The possible role of the pathognomically accumulated lipids (lipids containing SVLC fatty acids) in the process of demyelination will be examined by investigating their metabolism in peroxisomes from brain and modulation of the peroxisomal fatty acid metabolic pathway. These proposed studies will provide a better understanding of the normal metabolism of fatty acids in peroxisomes and will help elucidate the molecular interrelationships between abnormal peroxisomal lignoceroyl-CoA ligase activity and its pathological manifestations in X-ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022576-10
Application #
2264556
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-09
Project End
1997-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Pediatrics
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Shah, Navjot; Singh, Inderjit (2017) MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy. Mol Neurobiol 54:1392-1403
Nie, Xingju; Lowe, Danielle W; Rollins, Laura Grace et al. (2016) Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res 108:24-33
Baarine, Mauhamad; Beeson, Craig; Singh, Avtar et al. (2015) ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy. J Neurochem 133:380-96
Samuvel, Devadoss J; Saxena, Nishant; Dhindsa, Jasdeep S et al. (2015) AKP-11 - A Novel S1P1 Agonist with Favorable Safety Profile Attenuates Experimental Autoimmune Encephalomyelitis in Rat Model of Multiple Sclerosis. PLoS One 10:e0141781
Baarine, Mauhamad; Khan, Mushfiquddin; Singh, Avtar et al. (2015) Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy. PLoS One 10:e0143238
Khan, Mushfiquddin; Shunmugavel, Anandakumar; Dhammu, Tajinder S et al. (2015) Oral administration of cytosolic PLA2 inhibitor arachidonyl trifluoromethyl ketone ameliorates cauda equina compression injury in rats. J Neuroinflammation 12:94
Contreras, Miguel A; Alzate, Oscar; Singh, Avtar K et al. (2014) PPAR? activation induces N(?)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1. Lipids 49:119-31
Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Avtar K et al. (2013) Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-?-dependent mechanism. Glia 61:1500-1517
Paintlia, Ajaib S; Mohan, Sarumathi; Singh, Inderjit (2013) Combinatorial Effect of Metformin and Lovastatin Impedes T-cell Autoimmunity and Neurodegeneration in Experimental Autoimmune Encephalomyelitis. J Clin Cell Immunol 4:
Won, Je-Seong; Kim, Jinsu; Annamalai, Balasubramaniam et al. (2013) Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion. J Alzheimers Dis 34:621-35

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