title: Dysfunction of peroxisomes in twitcher mice brain: a possible mechanism of psychosine-induced disease.
abstract: Psychosine (galactosylsphingosine) accumulates in the brain of Krabbe disease (KD) patients as well as twitcher mice, a murine model of KD, resulting in loss of oligodendrocytes and myelin. This study documents progressive loss of peroxisomal proteins/functions and induction of expression of inflammatory cytokine TNF-alpha in twitcher brain. The observed decrease in peroxisomal proteins was accompanied by decreased level of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), one of the transcription factors required for expression of peroxisomal protein genes. The role of psychosine in down-regulation of PPAR-alpha activity was further supported by decreased PPAR-alpha mediated PPRE transcriptional activity in cells transfected with PPAR-alpha and PPRE reporters. The psychosine-induced down-regulation of PPAR activity and cell death was attenuated by sPLA2 inhibitor. Therefore, this study provides the first evidence of peroxisomal abnormality in a lysosomal disorder, suggesting that such dysfunction of peroxisomes may play a role in the pathogenesis of Krabbe disease.
authors.affiliation: Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Ehtishamul
authors.initials: E
authors.lastname: Haq
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Contreras
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000032:analysis / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000201:enzymology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D054501:Group II Phospholipases A2; D007965:Leukodystrophy, Globoid Cell / Q000139:chemically induced / Q000201:enzymology*; D051379:Mice; D008815:Mice, Inbred Strains; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000139:chemically induced / Q000201:enzymology*; D020675:Peroxisomes / Q000187:drug effects / Q000201:enzymology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011609:Psychosine / Q000378:metabolism* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D011609:Psychosine; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase; D010741:Phospholipases A; D054501:Group II Phospholipases A2