Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development
Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development
复制标题
DOI：
10.1093/hmg/ddy086
复制
发表时间：
2018-05-15
影响因子：
3.5
通讯作者：
Wirth, Brunhilde
中科院分区：
文献类型：
--
作者：
Carrera, Lilian A. Martinez;Gabriel, Elke;Wirth, Brunhilde
Bicaudal D2(BICD2)编码一个高度保守的运动适配器蛋白，在不同的细胞过程中调节动力蛋白-动力蛋白复合体。BICD2杂合突变导致常染色体显性遗传的下肢显性脊肌萎缩症-2(SMALED2)。尽管各种BICD2突变已经被证明可以改变与不同结合伙伴的相互作用或高尔基体的完整性，但SMALED2背后的BICD2突变的特定病理效应仍然不清楚。在这里，我们展示了来自患有SMALED2的个体的成纤维细胞显示出稳定的微管。重要的是，无论BICD2突变位于何处，都能观察到这种影响，这统一了影响微管的最可能的细胞机制。值得注意的是，在与疾病相关的细胞类型-运动神经元中，SMALED2导致BICD2突变的过表达也会导致微管稳定性增加，这伴随着轴突异常，如侧支分支和过度生长。为了研究BICD2突变在体内的病理后果，并解决其中两个突变是神经元还是肌肉特异的争议，我们建立了第一个SMALED2的果蝇模型。值得注意的是，BICD2突变体的神经元特异性表达导致幼虫的神经肌肉连接尺寸减小，成年果蝇的运动能力受损。相比之下，在肌肉中表达BICD2突变对运动功能没有明显影响，支持这种疾病的主要神经病因。因此，我们的发现有助于更好地理解SMALED2的病理学，为BICD2突变的共同病理机制提供了证据，BICD2突变增加了运动神经元中微管的稳定性，导致轴突分支增加和神经肌肉接头发育受损。
Bicaudal D2 (BICD2) encodes a highly conserved motor adaptor protein that regulates the dynein-dynactin complex in different cellular processes. Heterozygous mutations in BICD2 cause autosomal dominant lower extremity-predominant spinal muscular atrophy-2 (SMALED2). Although, various BICD2 mutations have been shown to alter interactions with different binding partners or the integrity of the Golgi apparatus, the specific pathological effects of BICD2 mutations underlying SMALED2 remain elusive. Here, we show that the fibroblasts derived from individuals with SMALED2 exhibit stable microtubules. Importantly, this effect was observed regardless of where the BICD2 mutation is located, which unifies the most likely cellular mechanism affecting microtubules. Significantly, overexpression of SMALED2-causing BICD2 mutations in the disease-relevant cell type, motor neurons, also results in an increased microtubule stability which is accompanied by axonal aberrations such as collateral branching and overgrowth. To study the pathological consequences of BICD2 mutations in vivo, and to address the controversial debate whether two of these mutations are neuron or muscle specific, we generated the first Drosophila model of SMALED2. Strikingly, neuron-specific expression of BICD2 mutants resulted in reduced neuromuscular junction size in larvae and impaired locomotion of adult flies. In contrast, expressing BICD2 mutations in muscles had no obvious effect on motor function, supporting a primarily neurological etiology of the disease. Thus, our findings contribute to the better understanding of SMALED2 pathology by providing evidence for a common pathomechanism of BICD2 mutations that increase microtubule stability in motor neurons leading to increased axonal branching and to impaired neuromuscular junction development.