黏脂贮积症IV型斑马鱼模型中的新型退行性和发育缺陷。
Novel degenerative and developmental defects in a zebrafish model of mucolipidosis type IV.
作者信息
Li Huiqing, Pei Wuhong, Vergarajauregui Sivia, Zerfas Patricia M, Raben Nina, Burgess Shawn M, Puertollano Rosa
机构信息
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
出版信息
Hum Mol Genet. 2017 Jul 15;26(14):2701-2718. doi: 10.1093/hmg/ddx158.
Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family. In this study, we used genome editing to knockout the two mcoln1 genes present in Danio rerio (zebrafish). Our model successfully reproduced the retinal and neuromuscular defects observed in MLIV patients, indicating that this model is suitable for studying the disease pathogenesis. Importantly, our model revealed novel insights into the origins and progression of the MLIV pathology, including the contribution of autophagosome accumulation to muscle dystrophy and the role of mcoln1 in embryonic development, hair cell viability and cellular maintenance. The generation of a MLIV model in zebrafish is particularly relevant given the suitability of this organism for large-scale in vivo drug screening, thus providing unprecedented opportunities for therapeutic discovery.
IV型黏脂贮积症（MLIV）是一种溶酶体贮积病，其特征为神经和眼科异常。目前尚无有效治疗方法。MLIV由MCOLN1基因突变引起，MCOLN1是一种来自瞬时受体电位（TRP）家族的溶酶体阳离子通道。在本研究中，我们使用基因组编辑技术敲除了斑马鱼中存在的两个mcoln1基因。我们的模型成功再现了MLIV患者中观察到的视网膜和神经肌肉缺陷，表明该模型适用于研究疾病发病机制。重要的是，我们的模型揭示了关于MLIV病理起源和进展的新见解，包括自噬体积累对肌肉营养不良的影响以及mcoln1在胚胎发育、毛细胞活力和细胞维持中的作用。鉴于这种生物适合进行大规模体内药物筛选，斑马鱼中MLIV模型的建立尤为重要，从而为治疗发现提供了前所未有的机会。
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