Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation
Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation
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DOI：
10.1038/emboj.2013.27
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
C. Waites;Sergio A. Leal-Ortiz;Nathan D. Okerlund;Hannah Dalke;Anna Fejtová;W. Altrock;E. Gundelfinger;C. Garner
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文献类型：
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作者：
C. Waites;Sergio A. Leal-Ortiz;Nathan D. Okerlund;Hannah Dalke;Anna Fejtová;W. Altrock;E. Gundelfinger;C. Garner
突触前活动区（AZ）是一个专门的微区，用于有效和重复释放神经递质。巴松管和短笛是AZ的两种高分子量组分，在其组装和结构维持中具有假设的作用。然而，缺乏这两种蛋白质的突触表现出相对较小的缺陷，可能是由于其显着的功能冗余。在目前的研究中，我们已经使用干扰RNA来消除这两种蛋白质从突触能突触，并发现它们是必不可少的维持突触的完整性。巴松管和短笛的缺失导致多种突触前蛋白质的异常降解，最终导致突触变性。这种表型部分由E3泛素连接酶Siah1介导，Siah1是Bassoon和Piccolo的相互作用伴侣，其活性由其保守的锌指结构域负调控。我们的研究结果证明了巴松管和短笛作为突触前泛素化和蛋白质稳态的关键调节因子的新作用。
The presynaptic active zone (AZ) is a specialized microdomain designed for the efficient and repetitive release of neurotransmitter. Bassoon and Piccolo are two high molecular weight components of the AZ, with hypothesized roles in its assembly and structural maintenance. However, glutamatergic synapses lacking either protein exhibit relatively minor defects, presumably due to their significant functional redundancy. In the present study, we have used interference RNAs to eliminate both proteins from glutamatergic synapses, and find that they are essential for maintaining synaptic integrity. Loss of Bassoon and Piccolo leads to the aberrant degradation of multiple presynaptic proteins, culminating in synapse degeneration. This phenotype is mediated in part by the E3 ubiquitin ligase Siah1, an interacting partner of Bassoon and Piccolo whose activity is negatively regulated by their conserved zinc finger domains. Our findings demonstrate a novel role for Bassoon and Piccolo as critical regulators of presynaptic ubiquitination and proteostasis.