VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function

In neurons, the continuous and dynamic endoplasmic reticulum (ER) network extends throughout the axon, and its dysfunction causes various axonopathies. However, it remains largely unknown how ER integrity and remodeling modulates presynaptic function in mammalian neurons. Here, we demonstrated that ER membrane receptors VAPA and VAPB are involved in modulating the synaptic vesicle (SV) cycle. VAP interacts with Secernin-1 (SCRN1) at the ER membrane via a single FFAT-like motif. Similar to VAP, loss of SCRN1 or SCRN1-VAP interactions resulted in impaired SV cycling. Consistently, SCRN1 or VAP depletion was accompanied in decreased action-potential evoked Ca2+ responses. Additionally, we found that VAP-SCRN1 interactions play an important role in maintaining ER continuity and dynamics, as well as presynaptic Ca2+ homeostasis. Based on these findings, we propose a model where the ER-localized VAP-SCRN1 interactions provide a novel control mechanism to tune ER remodeling, and thereby modulate Ca2+ dynamics and SV cycling at presynaptic sites. These data provide new insights in the molecular mechanisms controlling ER structure and dynamics, and highlight the relevance of ER function for SV cycling.

在神经元中，持续动态的内质网（endoplasmic reticulum, ER）网络贯穿整个轴突，其功能异常可引发多种轴突病变。然而，内质网的完整性与重塑如何调控哺乳动物神经元的突触前功能，目前仍知之甚少。本研究证实，内质网膜受体VAPA与VAPB参与调控突触囊泡（synaptic vesicle, SV）循环。VAP可通过单一FFAT样基序，与内质网膜上的分泌素-1（Secernin-1, SCRN1）发生相互作用。与VAP的表型一致，敲除SCRN1或破坏SCRN1-VAP的相互作用，均会导致突触囊泡循环受损。相应地，SCRN1或VAP的耗竭会伴随动作电位诱发的钙离子响应减弱。此外，我们发现VAP-SCRN1的相互作用对维持内质网的连续性与动态性，以及突触前钙离子稳态均发挥重要作用。基于上述研究结果，我们提出如下模型：定位于内质网的VAP-SCRN1相互作用提供了一种全新的调控机制，可调节内质网重塑，进而调控突触位点的钙离子动态与突触囊泡循环。本研究数据为调控内质网结构与动态性的分子机制提供了新见解，并凸显了内质网功能与突触囊泡循环的关联性。