Adrenoleukodystrophy (X-ALD) is a X-linked peroxisomal disorder which leads to neurological degeneration and is characterized by accumulation of very long chain (VLC) fatty acids (>C22). It is now demonstrated that this is due to impaired activity of peroxisomal VLC (Lignoceric acid) acyl-CoA ligase. The objectives of this proposal are to further understand the molecular basic of the abnormality in the peroxisomal metabolism of fatty acids and the mechanism of demyelination in X-ALD. this will be facilitated by purification of peroxisomal lignoceroyl-CoA ligase, the generation of polyclonal and monoclonal antibodies against it, and the isolation of a c- DNA will be used to measure the level of m-RNA in X-ALD tissues and the sequence analysis of the protein. The possible role of the pathognomic accumulation of lipids (lipids containing VLC fatty acids) in the process of demyelinization will be examined by investigating the proteolysis of proteins in isolated myelin membranes and synthetic membranes containing ALD lipids. constituents into membranes with the proper orientation for normal function in the cell is a subject of great interest. Studies concerning localization of lignoceroyl-CoA ligase will provide information as to it's topographical localization in the transverse plane of peroxisomal membranes. These studies will provide a better understanding of the normal metabolism of fatty acids in peroxisomes and help elucidate the molecular interrelationship 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 #
5R01NS022576-08
Application #
3405152
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-09
Project End
1993-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
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
Singh, Jaspreet; Khan, Mushfiquddin; Singh, Inderjit (2013) Caffeic acid phenethyl ester induces adrenoleukodystrophy (Abcd2) gene in human X-ALD fibroblasts and inhibits the proinflammatory response in Abcd1/2 silenced mouse primary astrocytes. Biochim Biophys Acta 1831:747-58
Won, Je-Seong; Kim, Jinsu; Paintlia, Manjeet Kaur et al. (2013) Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease. Brain Res 1508:44-52
Cheng, Gang; Palanisamy, Arun P; Evans, Zachary P et al. (2013) Cerulenin blockade of fatty acid synthase reverses hepatic steatosis in ob/ob mice. PLoS One 8:e75980

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