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.
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