Double-knockout mice for α- and β-synucleins:: Effect on synaptic functions
Double-knockout mice for α- and β-synucleins:: Effect on synaptic functions
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DOI：
10.1073/pnas.0406283101
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发表时间：
2004-10-12
影响因子：
11.1
通讯作者：
Südhof, TC
中科院分区：
文献类型：
--
作者：
Chandra, S;Fornai, F;Südhof, TC
一种丰富的突触前蛋白--α-突触核蛋白，在帕金森病的发病机制中发挥着重要作用。然而，关于α-突触核蛋白的正常功能存在矛盾的数据，可能是因为α-突触核蛋白与非常相似的β-突触核蛋白是冗余的。为了系统地研究突触核蛋白的功能，我们现在已经产生了缺乏α-和/或β-突触核蛋白的单敲除和双敲除（KO）小鼠。我们发现，小鼠突触核蛋白的缺失不会损害基本的脑功能或生存。我们没有发现突触核蛋白缺陷的突触，在短期或长期的突触可塑性，或在池的大小或再循环突触囊泡的补充的超微结构的显着变化。然而，蛋白质定量显示，KO的突触核蛋白引起两个小的突触信号蛋白，复合蛋白和14-3-3蛋白的选择性变化。此外，我们发现双基因敲除小鼠而非单基因敲除小鼠脑中的多巴胺水平降低了约20%。相反，血清素水平没有变化，多巴胺的摄取和释放从孤立的神经末梢是正常的。这些结果表明，突触核蛋白不是神经递质释放基本机制的重要组成部分，但可能有助于突触前功能的长期调节和/或维持。
An abundant presynaptic protein, alpha-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of a-synuclein, possibly because alpha-synuclein is redundant with the very similar beta-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack alpha- and/or beta-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by approximate to20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.