Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma 73104.
Department of Biological Sciences, University of Illinois at Chicago, Illinois 60607.
Genetics. 2018 Nov;210(3):947-968. doi: 10.1534/genetics.118.301466.
Synaptic vesicles (SVs) transmit signals by releasing neurotransmitters from specialized synaptic regions of neurons. In the synaptic region, SVs are tightly clustered around small structures called active zones. The motor KIF1A transports SVs outward through axons until they are captured in the synaptic region. This transport must be guided in the forward direction because it is opposed by the dynein motor, which causes SVs to reverse direction multiple times en route. The core synapse stability (CSS) system contributes to both guided transport and capture of SVs. We identified Sentryn as a CSS protein that contributes to the synaptic localization of SVs in Like the CSS proteins SAD Kinase and SYD-2 (Liprin-α), Sentryn also prevents dynein-dependent accumulation of lysosomes in dendrites in strains lacking JIP3. Genetic analysis showed that Sentryn and SAD Kinase each have at least one nonoverlapping function for the stable accumulation of SVs at synapses that, when combined with their shared functions, enables most of the functions of SYD-2 (Liprin-α) for capturing SVs. Also like other CSS proteins, Sentryn appears enriched at active zones and contributes to active zone structure, suggesting that it is a novel, conserved active zone protein. Sentryn is recruited to active zones by a process dependent on the active zone-enriched CSS protein SYD-2 (Liprin-α). Our results define a specialized group of active zone enriched proteins that can affect motorized transport throughout the neuron and that have roles in both guided transport and capture of SVs.
突触小泡（SVs）通过从神经元的特殊突触区域释放神经递质来传递信号。在突触区域，SVs 紧密聚集在称为活性区的小结构周围。马达蛋白 KIF1A 将 SVs 通过轴突向外运输，直到它们被捕获在突触区域。这种运输必须被导向正向，因为它受到动力蛋白马达的阻碍，动力蛋白马达使 SVs 在运输过程中多次反转方向。核心突触稳定性（CSS）系统有助于 SVs 的导向运输和捕获。我们发现 Sentryn 是一种 CSS 蛋白，有助于 SVs 在突触中的定位。与 CSS 蛋白 SAD 激酶和 SYD-2（Liprin-α）一样，Sentryn 还防止动力蛋白依赖性的溶酶体在缺乏 JIP3 的菌株中在树突中的积累。遗传分析表明，Sentryn 和 SAD 激酶各自至少具有一个非重叠的功能，可使 SVs 在突触中稳定积累，当与它们的共享功能结合时，使 SYD-2（Liprin-α）的大部分捕获 SVs 的功能成为可能。与其他 CSS 蛋白一样，Sentryn 似乎在活性区富集，并有助于活性区结构，表明它是一种新型的保守活性区蛋白。Sentryn 通过依赖富含活性区的 CSS 蛋白 SYD-2（Liprin-α）的过程被募集到活性区。我们的结果定义了一组特殊的富含活性区的蛋白质，它们可以影响整个神经元中的马达驱动运输，并在 SVs 的导向运输和捕获中发挥作用。
