title: Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies.
abstract: This study was designed to understand the role of inflammatory mediators involved in the neurobiology of childhood adrenoleukodystrophy (cALD) by comparing the differential expression of the inflammatory mediators with metabolite very long chain fatty acids that accumulate in this disease. Histopathological examinations indicated extensive demyelination and accumulation of infiltrates in perivascular cuffs in plaque area (PA) and inflammatory area (IA) compared to normal looking area (NLA) of the cALD brain and controls. The PA had excessive accumulation of cholesterol ester (25-30-fold), VLC fatty acids (8-12-fold), and exhaustive depletion of cholesterol (60-70%) and sphingomyelin (50-55%) in comparison to controls. The mRNA expression of cytokines (IL-1alpha, IL-2, IL-3, IL-6, TNF-alpha, and GM-CSF), chemokines (CCL2, -4, -7, -11, -16, -21, -22, CXCL1, CX3CL1, and SDF-2) and iNOS in IA was significantly increased compared to NLA of the cALD and controls determined by gene array, semiquantitative RT-PCR, and immunohistochemistry. These results indicate that accumulation of VLC fatty acid contents in membrane domains associated with signal transduction pathways may trigger the inflammatory process through activation of resident glial cells (microglia and astrocytes) resulting in loss of myelin and oligodendrocytes.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Ajaib Singh
authors.initials: AS
authors.lastname: Paintlia
authors.forename: Anne Genevieve
authors.initials: AG
authors.lastname: Gilg
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
authors.forename: Avtar Kaur
authors.initials: AK
authors.lastname: Singh
authors.forename: Ernest
authors.initials: E
authors.lastname: Barbosa
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000326:Adrenoleukodystrophy / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002648:Child; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008970:Molecular Weight; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D013109:Sphingomyelins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018925:Chemokines; D016207:Cytokines; D005227:Fatty Acids; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D013109:Sphingomyelins; D002784:Cholesterol; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II