Dysfunction of peroxisomes in twitcher mice brain: A possible mechanism of psychosine-induced disease
Journal Article
·
· Biochemical and Biophysical Research Communications
- Department of Pediatrics and The Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425 (United States)
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425 (United States)
Psychosine (galactosylsphingosine) accumulates in 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 sPLA{sub 2} inhibitor. Therefore, this study provides 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.
- OSTI ID:
- 20798923
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 343; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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