Hogg James A, Cousin Michael A
Centre for Discovery Brain Sciences, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh, Scotland, UK.
Simons Initiative for the Developing Brain, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh, Scotland, UK.
J Neurochem. 2025 Jan;169(1):e16308. doi: 10.1111/jnc.16308.
Synaptic vesicle protein 2A (SV2A) is an abundant synaptic vesicle cargo with an as yet unconfirmed role in presynaptic function. It is also heavily implicated in epilepsy, firstly being the target of the leading anti-seizure medication levetiracetam and secondly with loss of function mutations culminating in human disease. A range of potential presynaptic functions have been proposed for SV2A; however its interaction with the calcium sensor for synchronous neurotransmitter release, synaptotagmin-1 (Syt1), has received particular attention over the past decade. In this review we will assess the evidence that the primary role of SV2A is to control the expression and localisation of Syt1 at the presynapse. This will integrate biochemical, cell biological and physiological studies where the interaction, trafficking and functional output of Syt1 is altered by SV2A. The potential for SV2A-dependent epilepsy to be a result of dysfunctional Syt1 expression and localisation is also discussed. Finally, a series of key open questions will be posed that require resolution before a definitive role for SV2A in Syt1 function in health and disease can be confirmed.
突触囊泡蛋白2A（SV2A）是一种丰富的突触囊泡货物蛋白，其在突触前功能中的作用尚未得到证实。它也与癫痫密切相关，首先它是主要抗癫痫药物左乙拉西坦的作用靶点，其次功能丧失突变最终会导致人类疾病。人们已经提出了一系列SV2A潜在的突触前功能；然而，在过去十年中，它与用于同步神经递质释放的钙传感器——突触结合蛋白-1（Syt1）的相互作用受到了特别关注。在这篇综述中，我们将评估证据，以证明SV2A的主要作用是控制Syt1在突触前的表达和定位。这将整合生化、细胞生物学和生理学研究，其中Syt1的相互作用、运输和功能输出会因SV2A而改变。我们还将讨论SV2A依赖性癫痫可能是由于Syt1表达和定位功能失调所致。最后，我们将提出一系列关键的开放性问题，在确定SV2A在健康和疾病状态下Syt1功能中的明确作用之前，这些问题需要得到解决。
