Abstract
Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of the loss of oligodendrocytes and myelin in krabbe disease (KD) remains unclear. Here, we addressed how oligodendrocytes are induced by psychosine treatment in both KG-1C human oligodendroglial cells and mouse oligodendrocyte precursor cells. We found that fatty acid binding protein 5 (FABP5) expressed in oligodendrocytes accelerates mitochondria-induced glial death by inducing mitochondrial macropore formation through voltage-dependent anion channels (VDAC-1) and BAX. These two proteins mediate mitochondrial outer membrane permeabilization, thereby leading to the release of mitochondrial DNA and cytochrome C into the cytosol, and the activation of apoptotic caspases. Furthermore, we confirmed that the inhibition of FABP5 functions by shRNA and FABP5-specific ligands blocking mitochondrial macropore formation, thereby rescuing psychosine-induced oligodendrocyte death. Taken together, we identified FABP5 as a critical factor in mitochondrial injury associated with psychosine-induced apoptosis in oligodendrocytes.
Highlights
Oligodendrocytes are myelinating glial cells in the central nervous system (CNS) that constitute about 5–10% of the total glial population, and are critical for rapid action potential propagation and metabolic support of neurons [1,2]
BAX slightly shifted to fractions 9 and 10 (Figure 3F,G). These results indicate that fatty acid binding protein 5 (FABP5) participates in mitochondrial pore formation with voltage-dependent anion channel 1 (VDAC-1) oligomerization
Since we found that psychosine toxicity towardsToxicity mitochondria required FABP5, it is necessary to Inhibition of FABP5 in Psychosine define the effect of pharmacological inhibition of FABP5 by FABP5 inhibitors on psychosine toxicity
Summary
Oligodendrocytes are myelinating glial cells in the central nervous system (CNS) that constitute about 5–10% of the total glial population, and are critical for rapid action potential propagation and metabolic support of neurons [1,2]. Psychosine mediates several toxic effects via mitochondria, including inhibition of the electron transport chain, oxidative phosphorylation, and calcium transport [5], thereby triggering cytochrome C release and loss of mitochondrial membrane potential, which in turn results in oligodendrocyte apoptosis [6]. FABP5 inhibition suppresses IL-17 cytokine production and skews T cells toward a Treg phenotype in regulatory T cells (Tregs) [17]. This is consistent with the observation that FABP5 inhibition causes reduced clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mouse models. We focused on the critical role of FABP5 in eliciting mitochondria-mediated apoptosis by inducing mitochondrial macropore formation with VDAC-1 and BAX. FABP5 inhibition represents a potential therapeutic approach for treating diseases associated with psychosine toxicity
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