The goal of this proposal is to investigate the mechanisms of very long chain fatty acid (VLCFA;>C22:0) induced neuroinflammatory demyelinating disease and to evaluate the efficacy of interventions of these signaling pathways as possible therapeutics for X-Adrenoleukodystrophy (X-ALD). X-ALD, the most common inherited peroxisomal disorder, is caused by pathognomonic accumulation of VLCFA as a result of peroxisomal dysfunction leading to loss of oligodendrocytes and myelin and a shortened life expectancy. The complexities in the transition of inherited metabolic disease into neuroinflammatory disease of X-ALD have frustrated the efforts of various laboratories including ours, to establish the relationship between VLCFA accumulation and induction of the neuroinflammation. By using a comprehensive approach including proteomics and lipidomics on cells (fibroblasts) and autopsy brain from X-ALD and brain cells (astrocytes and oligodendrocytes) from control and X-ALD mice, we have investigated the molecular events associated with the development of neuroinflammatory disease in X-ALD, establishing for the first time, that excessive accumulation of VLCFA induces cellular signaling for inflammatory response in astrocytes and excessive accumulation of VLCFA in the presence of inflammatory mediators induces cellular signaling for apoptotic loss of oligodendrocytes. Based on these observations, we hypothesize that pathognomonic accumulation of VLCFA, as a constituent of different lipids (sphingomyelin/ceramide/lactosylceramide), induces differential signal transduction pathways for sustained inflammatory response in astrocytes and signals for apoptotic loss of oligodendrocytes in X-ALD. The proposed studies are:
Specific Aim 1 : To elucidate the mechanisms of VLCFA-induced inflammatory response in astrocytes in the X-ALD setting.
Specific Aim 2 : To elucidate the mechanisms of VLCFA-induced cell death of oligodendrocytes in the setting of X-ALD disease.
Specific Aim 3 : To evaluate the therapeutic efficacy of compounds (as therapeutics) that attenuate VLCFA derangement induced pathways in astrocytes and oligodendrocytes. The studies on the differential role of VLCFA containing lipids in astrocytes vs. oligodendrocytes are innovative. Understanding the mechanisms of VLCFA-induced inflammatory response in astrocytes and cell death in oligodendrocytes is critical for the development of effective therapy for X-ALD.

Public Health Relevance

X-ALD, the most common genetic disorder of peroxisomes, affects boys in early childhood due to the pathognomonic accumulation of VLCFA. It is also known as Lorenzo's disease based on a movie called Lorenzo's Oil depicting the life of a child suffering from X-ALD. The mutation in ALD gene results in metabolic disease as excessive accumulation of VLCFA, which subsequently leads to neuroinflammatory disease, loss of oligodendrocytes/myelin and a shortened life span. Unfortunately, there is no effective therapy to control neurological disease. Children with X-ALD die within 1-3 years of onset of the neurological disease. The proposed studies are designed to delineate the molecular mechanisms of VLCFA derangement induced signaling that induces the inflammatory response in astrocytes and cell death in oligodendrocytes. Understanding these mechanisms is critical for the development of effective therapy for X-ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022576-29
Application #
8631101
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Morris, Jill A
Project Start
1985-09-09
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
29
Fiscal Year
2014
Total Cost
$284,584
Indirect Cost
$91,646
Name
Medical University of South Carolina
Department
Pediatrics
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Contreras, Miguel A; Alzate, Oscar; Singh, Avtar K et al. (2014) PPAR* activation induces N(ýý)-Lys-acetylation of rat liver peroxisomal multifunctional enzyme type 1. Lipids 49:119-31
Paintlia, Ajaib S; Paintlia, Manjeet K; Mohan, Sarumathi et al. (2013) AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am J Pathol 183:526-41
Singh, Jaspreet; Khan, Mushfiquddin; Pujol, Aurora et al. (2013) Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells. PLoS One 8:e70712
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 61:1500-17
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
Paintlia, Manjeet K; Paintlia, Ajaib S; Singh, Avtar K et al. (2013) S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions. J Biol Chem 288:3831-43
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
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:
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
Shunmugavel, Anandakumar; Khan, Mushfiquddin; Chou, Peter C-te et al. (2012) Spinal cord injury induced arrest in estrous cycle of rats is ameliorated by S-nitrosoglutathione: novel therapeutic agent to treat amenorrhea. J Sex Med 9:148-58

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