DataSheet1_A Drosophila model for Meniere’s disease: Dystrobrevin is required for support cell function in hearing and proprioception.pdf

Meniere’s disease (MD) is an inner ear disorder characterised by recurrent vertigo attacks associated with sensorineural hearing loss and tinnitus. Evidence from epidemiology and Whole Exome Sequencing (WES) suggests a genetic susceptibility involving multiple genes, including α-Dystrobrevin (DTNA). Here we investigate a Drosophila model. We show that mutation, or knockdown, of the DTNA orthologue in Drosophila, Dystrobrevin (Dyb), results in defective proprioception and impaired function of Johnston’s Organ (JO), the fly’s equivalent of the inner ear. Dyb and another component of the dystrophin-glycoprotein complex (DGC), Dystrophin (Dys), are expressed in support cells within JO. Their specific locations suggest that they form part of support cell contacts, thereby helping to maintain the integrity of the hemolymph-neuron diffusion barrier, which is equivalent to a blood-brain barrier. These results have important implications for the human condition, and notably, we note that DTNA is expressed in equivalent cells of the mammalian inner ear.

梅尼埃病（Meniere’s disease, MD）是一种内耳疾病，以反复发作的眩晕发作伴感音神经性听力损失与耳鸣为典型特征。流行病学及全外显子组测序（Whole Exome Sequencing, WES）相关证据提示，该病存在涉及多基因的遗传易感性，其中涵盖α-肌营养不良蛋白（α-Dystrobrevin, DTNA）。本研究对果蝇模型展开探究，结果显示：果蝇体内DTNA的同源基因——肌营养不良蛋白（Dystrobrevin, Dyb）发生突变或基因敲低后，会引发本体感觉缺陷，同时导致作为果蝇内耳等效结构的江氏器（Johnston’s Organ, JO）功能受损。Dyb与肌营养不良蛋白-糖蛋白复合物（dystrophin-glycoprotein complex, DGC）的另一组分肌营养不良蛋白（Dystrophin, Dys）均在江氏器的支持细胞中表达。二者的特异性定位表明，它们参与构成支持细胞间的连接结构，进而助力维持血淋巴-神经扩散屏障的完整性——该屏障与哺乳动物的血脑屏障功能等效。上述研究结果对人类相关疾病具有重要的临床启示价值，值得注意的是，我们发现DTNA在哺乳动物内耳的对应细胞中同样存在表达。