Dysfunction of peroxisomes in twitcher mice brain: A possible mechanism of psychosine-induced disease

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-α in twitcher brain. The observed decrease in peroxisomal proteins was accompanied by decreased level of peroxisome proliferator-activated receptor-alpha (PPAR-α), one of the transcription factors required for expression of peroxisomal protein genes. The role of psychosine in down-regulation of PPAR-α activity was further supported by decreased PPAR-α mediated PPRE transcriptional activity in cells transfected with PPAR-α 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.