Huntingtin-deficient zebrafish exhibit defects in iron utilization and development

摘要: Huntington's disease (HD) is one of nine neurodegenerative disorders caused by expansion CAG repeats encoding polyglutamine in their respective, otherwise apparently unrelated proteins. Despite these proteins having widespread and overlapping expression patterns the brain, a specific unique subset neurons exhibits particular vulnerability each disease. It has been hypothesized that perturbation normal protein function contributes to specificity neuronal vulnerability; however, biological functions many including HD gene product, Huntingtin (Htt), are unclear. To explore roles Htt, we have used antisense morpholino oligonucleotides observe effects Htt deficiency early zebrafish development. Knockdown resulted variety developmental defects. Most notably, Htt-deficient had hypochromic blood due decreased hemoglobin production, despite presence iron within cells. Furthermore, transferrin receptor 1 transcripts were increased, suggesting cellular starvation. Provision cytoplasm bio-available form restored production embryos. Since erythroid cells acquire via receptor-mediated endocytosis transferrin, results suggest role for making endocytosed accessible utilization. Iron required oxidative energy defects homeostasis metabolism features pathogenesis most pronounced major region neurodegeneration. therefore plausible Htt's pathway (by tract expansion) pathology, particularly its specificity.