Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy
Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy
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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
DOI：
10.1101/854711
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Rossor A
中科院分区：
文献类型：
--
作者：
Rossor A
BICD2常染色体显性遗传错义突变可导致运动神经元发育性疾病--脊髓肌萎缩症2(SMALED2)。BICD2是细胞质dynein/dynactin运动复合体的关键成分，在轴突中驱动微管依赖的细胞内货物向胞体逆行运输。具有BICD2病理性突变的患者会出现类似于Bicd2基因敲除(−/−)小鼠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性Bicd2−/−小鼠的运动神经元表型。与野生型小鼠相比，Bicd2−/−小鼠L4腹根大口径运动神经元的数量显着减少。肌肉特异的Bicd2基因敲除导致L4腹侧轴突减少，与全局Bicd2−/−小鼠相似。Rab6是BICD2的主要结合伙伴，它是一个小的GTP酶，用于将胞外囊泡从反式高尔基体网络分选到质膜上。因此，我们研究了SMALED2患者成纤维细胞的分泌途径，并使用VSV-G报告程序证明了BICD2是构成分泌货物从跨高尔基网络到质膜的生理流动所必需的。综上所述，这些数据表明，肌肉中BICD2的缺失是运动神经系统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。
Autosomal dominant missense mutations inBICD2cause 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 inBICD2develop malformations of cortical and cerebellar development similar toBicd2knockout (−/−) mice. In this study we sought to re-examine the motor neuron phenotype of conditionalBicd2−/−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 ofBicd2results in a similar reduction in L4 ventral axons comparable to globalBicd2−/−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.
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影响因子：
3.7
作者：
Sutcliffe B;Forero MG;Zhu B;Robinson IM;Hidalgo A
通讯作者：
Hidalgo A
影响因子：
11.8
作者：
Grigoriev, Ilya;Splinter, Daniel;Akhmanova, Anna
通讯作者：
Akhmanova, Anna
影响因子：
14.5
作者：
Rossor, Alexander M.;Oates, Emily C.;North, Kathryn N.
通讯作者：
North, Kathryn N.
影响因子：
3.5
作者：
Carrera, Lilian A. Martinez;Gabriel, Elke;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
9.8
作者：
Oates, Emily C.;Rossor, Alexander M.;Reilly, Mary M.
通讯作者：
Reilly, Mary M.