Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (-/-) mice. In this study we sought to re-examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of large calibre motor neurons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2 results in a similar reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of exocytic vesicles from the Trans Golgi Network to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated that BICD2 is required for physiological flow of constitutive secretory cargoes from the Trans Golgi Network to the plasma membrane using a VSV-G reporter assay. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology in the motor nervous system, which has important implications for future therapeutic approaches in SMALED2.

中文翻译：

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肌肉中 BICD2 的缺失会导致脊髓性肌萎缩症发育过程中运动神经元的缺失。

BICD2 的常染色体显性错义突变会导致脊髓性肌萎缩下肢为主 2 (SMALED2)，这是一种运动神经元发育性疾病。BICD2 是细胞质动力蛋白/动力蛋白运动复合体的关键组成部分，它在轴突中驱动细胞内货物向细胞体的微管依赖性逆行运输。BICD2 发生病理突变的患者会出现与 Bicd2 敲除 (-/-) 小鼠相似的皮质和小脑发育畸形。在这项研究中，我们试图重新检查条件 Bicd2-/- 小鼠的运动神经元表型。与野生型小鼠相比，Bicd2-/- 小鼠 L4 腹侧根大口径运动神经元的数量显着减少。Bicd2 的肌肉特异性敲除导致 L4 腹侧轴突的减少，与整体 Bicd2-/- 小鼠相当。Rab6 是一种小型 GTP 酶，用于将胞吐囊泡从跨高尔基体网络分选到质膜，是 BICD2 的主要结合伴侣。因此，我们检查了 SMALED2 患者成纤维细胞中的分泌途径，并使用 VSV-G 报告基因测定证明了 BICD2 是组成型分泌货物从高尔基体网络到质膜的生理流动所必需的。总之，这些数据表明，肌肉中的 BICD2 丢失是运动神经系统中非细胞自主病理的主要驱动因素，这对 SMALED2 的未来治疗方法具有重要意义。