Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Sci Transl Med. 2017 Oct 25;9(413). doi: 10.1126/scitranslmed.aaj2347.
Friedreich's ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.
弗里德赖希共济失调（FRDA）是一种不可治愈的常染色体隐性神经退行性疾病，由基因中的内含子 GAA 重复扩展导致线粒体蛋白 frataxin 的表达减少引起。我们报告了将野生型小鼠造血干细胞和祖细胞（HSPC）移植到 FRDA 的 YG8R 小鼠模型中的治疗效果。在 HSPC 移植的 YG8R 小鼠中，肌肉无力和运动缺陷的发展被阻止，背根神经节（DRG）中大感觉神经元的退化以及大脑、骨骼肌和心脏中的线粒体容量得到改善。移植的 HSPC 在大脑和脊髓中分化为小胶质细胞，在 DRG、心脏和肌肉中分化为巨噬细胞。我们观察到从 HSPC 衍生的小胶质细胞/巨噬细胞向 FRDA 小鼠神经元和肌细胞体内转移野生型 frataxin 和 Cox8 线粒体蛋白。我们的结果表明，HSPC 介导的 YG8R 小鼠 FRDA 的表型挽救，这表明应该进一步研究这种方法作为治疗 FRDA 的策略。
