Delineation of the pathogenic presynaptic mechanisms of synaptotagmin-1 variants
Delineation of the pathogenic presynaptic mechanisms of synaptotagmin-1 variants
复制标题
synaptotagmin-1 变体致病性突触前机制的描述
DOI：
10.1101/2023.10.29.564558
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Melland H
中科院分区：
文献类型：
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作者：
Melland H
突触前钙传感器synaptotagmin-1（SYT 1）中的错义变体与常染色体显性遗传神经发育障碍（NDD）相关。这些以突变特异性方式导致诱发的神经递质释放的显性负性损伤;然而，NDD相关变体是否也扰乱SYT 1的辅助功能仍不清楚。我们研究了SYT 1变体在培养的海马神经元中的表达是否改变了动作电位独立的自发突触囊泡胞吐或突触囊泡胞吞。SYT 1变异体没有诱导显性负性损伤的过程中，确认有缺陷的诱发胞吐是SYT 1相关的NDD的主要致病机制。为了研究人类变异体对诱发胞吐的差异影响，使用NDD相关突变和策略突变来探索C2B结构域中两个不同的Ca 2+结合残基的功能重要性。我们表明，这两个性质的氨基酸变化和特定的残基的目标确定的严重程度外排紊乱。总之，这项工作为理解SYT 1功能提供了信息，并进一步阐明了治疗SYT 1相关NDD的潜在机制靶点。
Missense variants in the presynaptic calcium sensor synaptotagmin-1 (SYT1) are associated with an autosomal dominant neurodevelopmental disorder (NDD). These cause dominant-negative impairment of evoked neurotransmitter release in a mutation-specific manner; however, whether NDD-associated variants also perturb the auxiliary functions of SYT1 remains unknown. We investigated whether the expression of SYT1 variants in cultured hippocampal neurons altered either action potential-independent spontaneous synaptic vesicle exocytosis or synaptic vesicle endocytosis. SYT1 variants did not induce dominant-negative impairment of either process, confirming that defective evoked exocytosis is the major pathogenic mechanism of SYT1-associated NDD. To examine the differential impacts of human variants on evoked exocytosis, both NDD-associated and strategic mutations were used to explore the functional importance of two distinct Ca2+-binding residues in the C2B domain. We show that both the nature of the amino acid change and the specific residues targeted determine the severity of exocytic disturbance. Together, this work informs understanding of SYT1 function and further clarifies potential mechanistic targets for treating SYT1-associated NDD.