Department of Cell Biology, University of Alabama School of Medicine, Birmingham, AL 35294, USA.
Dev Cell. 2012 Feb 14;22(2):348-62. doi: 10.1016/j.devcel.2011.12.009. Epub 2012 Jan 19.
The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.
VAPB/ALS8 主要精子蛋白结构域（vMSP）与肌萎缩侧索硬化症和脊髓性肌萎缩症有关，但它在神经系统中的功能尚不清楚。在秀丽隐杆线虫和果蝇中，vMSP 从其跨膜锚定中切割下来，并以细胞类型特异性的方式分泌。我们表明，神经元分泌的 vMSP 作用于在横纹肌中表达的 Lar 样蛋白酪氨酸磷酸酶和 Roundabout 生长锥导向受体。这种信号通路促进 Arp2/3 依赖性肌动蛋白重塑和线粒体定位到富含肌动蛋白的肌 I 带。秀丽隐杆线虫 VAPB 突变体的线粒体定位、形态、迁移和分裂/融合缺陷可被 Lar 样受体或 Arp2/3 失活所抑制。因此，重塑肌动蛋白细胞骨架的生长锥导向受体途径对线粒体动力学有意外影响。我们提出，神经元分泌 vMSP 以促进横纹肌的能量产生和代谢，部分是通过调节线粒体的定位和功能。
