Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.
Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.
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DOI：
10.1186/s12915-016-0248-3
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发表时间：
2016-03-31
期刊：
影响因子：
5.4
通讯作者：
Berezovska O
中科院分区：
文献类型：
--
作者：
Kuzuya A;Zoltowska KM;Post KL;Arimon M;Li X;Svirsky S;Maesako M;Muzikansky A;Gautam V;Kovacs D;Hyman BT;Berezovska O
突触损失与记忆力衰退密切相关。由于神经元活动异常，β 淀粉样蛋白 (Aβ) 肽，特别是神经毒性 Aβ42 的局部积累可能是突触功能障碍、神经退行性变和记忆障碍的基础。为了深入了解突触神经元活动调节 Aβ 产生的分子事件，我们探索了新发现的阿尔茨海默病相关早老素 1 (PS1)/γ-分泌酶和突触小泡蛋白之间钙依赖性相互作用的功能结果。小鼠脑裂解物的质谱筛选鉴定出突触结合蛋白 1 (Syt1) 是一种新型突触特异性 PS1 结合伴侣，在体外和体内显示出 Ca2+ 依赖性 PS1 结合谱。我们发现 Aβ 水平，更重要的是 PS1 的构象和 Aβ42/40 比率，受到 Syt1 过表达或敲低的影响，表明 Syt1 及其与 PS1 的相互作用可能调节突触处的 Aβ 产生。此外，在 Syt1 缺失的情况下，β-分泌酶 1 (BACE1) 稳定性、β-和 γ-分泌酶活性以及 PS1 和 BACE1 的细胞内区室化发生改变，但淀粉样前体蛋白 (APP)、尼卡斯特林 (Nct)、早老素增强剂 2 (Pen-2) 或突触素 (Syp) 的细胞内区室化没有改变，表明 Syt1 对 PS1 和 BACE1 的选择性作用贩运。我们的研究结果表明 Syt1 是一种新型 Ca2+ 敏感 PS1 调节剂，可以调节突触 Aβ，为新型选择性突触靶向治疗策略开辟了途径。本文的在线版本 (doi:10.1186/s12915-016-0248-3) 包含补充材料，可供授权用户使用。
Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aβ production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer’s disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins. Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca2+-dependent PS1 binding profiles in vitro and in vivo. We found that Aβ level, and more critically, conformation of the PS1 and the Aβ42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aβ production at the synapse. Moreover, β-secretase 1 (BACE1) stability, β- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking. Our findings identify Syt1 as a novel Ca2+-sensitive PS1 modulator that could regulate synaptic Aβ, opening avenues for novel and selective synapse targeting therapeutic strategies. The online version of this article (doi:10.1186/s12915-016-0248-3) contains supplementary material, which is available to authorized users.