Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis.

Myelin is a specialized membrane that wraps around nerve fibers and is essential for normal axonal conduction in neurons. In the central nervous system, oligodendrocytes are responsible for myelin formation. Recent studies have reported pathological abnormalities in oligodendrocytes in human patients with amyotrophic lateral sclerosis (ALS) and a mouse model of ALS expressing the G93A mutation of the human superoxide dismutase 1 (mtSOD1). However, it is unclear whether oligodendrocyte pathology in ALS represents the primary dysfunction induced by mtSOD1 and how mtSOD1 contributes to oligodendrocyte degeneration and ALS pathogenesis. We analyzed GAL4-VP16-UAS transgenic zebrafish selectively expressing mtSOD1 in mature oligodendrocytes. We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration. Pathological changes observed in this transgenic zebrafish were similar to the pathology observed in the SOD1G93A mouse model of ALS, which is characterized by expression of mtSOD1 in all cells. In addition, oligodendrocyte dysfunction induced by mtSOD1 was associated with anxiety-related behavioral abnormalities, learning impairments, and motor defects in the early symptomatic stage. We also found that treatment with potassium channel inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, suggesting that myelin disruption induces behavioral abnormalities independently of MCT1. These results indicate that mtSOD1-induced dysfunction of mature oligodendrocytes is sufficient to induce motor neuron degeneration, thus informing future therapeutic strategies targeted at oligodendrocytes in ALS.

UVB induces HIF-1α-dependent TSLP expression via the JNK and ERK pathways.

Thymic stromal lymphopoietin (TSLP) may have a key role in the initiation and maintenance of allergic inflammatory diseases, including atopic dermatitis. The present study revealed that UVB radiation exposure could induce TSLP expression in human keratinocytes and a human skin equivalent model. In addition, we investigated the regulatory mechanism of UVB-induced TSLP expression in keratinocytes. TSLP expression was upregulated by transfection with pcDNA3-hypoxia-inducible factor (HIF)-1α (P402A and P564A), which stably expresses HIF-1α protein. UVB-induced TSLP induction in keratinocytes was suppressed in the treatment of mitogen-activated protein kinase inhibitors or small interfering RNAs against HIF-1α. The results of chromatin immunoprecipitation assays indicate the direct involvement of HIF-1α in UVB-mediated TSLP induction. Taken together, these findings indicate that UVB exposure may increase TSLP expression through a HIF-1α-dependent mechanism via the c-JUN N-terminal kinase and extracellular signal-regulated kinase pathways in human keratinocytes. Our data showed that UVB-induced TSLP might increase secretion of the T-helper type 2-attracting chemokine (c-c motif) ligand 17 by human dendritic cells. The present study suggests an important role of HIF-1α in UVB-mediated immune response in keratinocytes.