Limb-girdle muscular dystrophy D2 (LGMDD2) is an ultrarare autosomal dominant myopathy caused by mutation of the normal stop codon of the TNPO3 nuclear importin. The mutant protein carries a 15 amino acid C-terminal extension associated with pathogenicity. Here we report the first animal model of the disease by expressing the human mutant TNPO3 gene in Drosophila musculature or motor neurons and concomitantly silencing the endogenous expression of the fly protein ortholog. A similar genotype expressing wildtype TNPO3 served as a control. Phenotypes characterization revealed that mutant TNPO3 expression targeted at muscles or motor neurons caused LGMDD2-like phenotypes such as muscle degeneration and atrophy, and reduced locomotor ability. Notably, LGMDD2 mutation increase TNPO3 at the transcript and protein level in the Drosophila model Upregulated muscle autophagy observed in LGMDD2 patients was also confirmed in the fly model, in which the anti-autophagic drug chloroquine was able to rescue histologic and functional phenotypes. Overall, we provide a proof of concept of autophagy as a target to treat disease phenotypes and propose a neurogenic component to explain mutant TNPO3 pathogenicity in diseased muscles.

中文翻译：

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抑制自噬可挽救 LGMDD2 果蝇模型中的肌肉萎缩

肢带型肌营养不良症 D2 (LGMDD2) 是一种极罕见的常染色体显性遗传性肌病，由TNPO3核输入蛋白的正常终止密码子突变引起。突变蛋白携带与致病性相关的 15 个氨基酸的 C 端延伸。在这里，我们通过在果蝇肌肉组织或运动神经元中表达人类突变TNPO3基因并同时沉默果蝇蛋白直向同源物的内源性表达来报告该疾病的第一个动物模型。表达野生型TNPO3 的类似基因型用作对照。表型表征表明突变体TNPO3针对肌肉或运动神经元的表达导致 LGMDD2 样表型，如肌肉退化和萎缩，并降低运动能力。值得注意的是，果蝇模型中LGMDD2 突变增加了转录本和蛋白质水平的 TNPO3 在果蝇模型中观察到的 LGMDD2 患者肌肉自噬上调也得到证实，其中抗自噬药物氯喹能够挽救组织学和功能表型。总体而言，我们提供了自噬作为治疗疾病表型的目标的概念证明，并提出了神经源性成分来解释患病肌肉中突变的 TNPO3 致病性。