Proteasome-dependent regulation of active zone proteins in activity-induced plasticity of presynaptic function

活性区蛋白在活性诱导的突触前功能可塑性中的蛋白酶体依赖性调节

• 批准号: 217676110
• 负责人: Professorin Dr. Anna Fejtová
• 金额: --
• 依托单位: Psychiatrische und Psychotherapeutische Klinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/217676110?language=en
• 关键词: Proteasome; dependent; regulation; active; zone

Functional plasticity of neurotransmitter release is a cellular mechanism underlying complex brain functions such as learning and memory formation. Synaptic transmission is based on a precisely controlled sequence of molecular interactions and it is therefore plausible that the functional changes occurring during synaptic plasticity are connected with the molecular remodeling of involved synaptic machineries. The components of the cytomatrix at the active zone (CAZ) are involved in the spatial organization and functional regulation of the neurotransmitter release from the presynaptic boutons. Our previous studies have shown that activity-induced remodeling of the CAZ involves both de novo synthesis as well as ubiquitin-proteasome system- (UPS-) dependent degradation of CAZ proteins. This project is designed to study the cellular and molecular mechanisms controlling this UPS-dependent regulation of the CAZ and its role in activity-induced presynaptic plasticity. To this end will study the molecular interaction of CAZ proteins Bassoon and liprin-with ubiquitin-conjugating E3 enzymes and with subunits of the proteasome. We will investigate the role of these interactions in the regulation of UPS-dependent degradation of target proteins and consecutively in the modulation of presynaptic function. Moreover, we plan to perform imaging studies of activity-dependent modulation of proteasomal dynamic localization and processivity in axons and presynaptic boutons. This study will gain new insights into UPS-dependent mechanisms underlying activity-dependent remodeling of the CAZ during experience-induced and homeostatic synaptic plasticity.

神经递质释放的功能可塑性是复杂脑功能（如学习和记忆形成）的细胞机制。突触传递是基于精确控制的分子相互作用序列，因此，突触可塑性过程中发生的功能变化与相关突触机制的分子重塑有关是合理的。活动区的细胞基质成分参与突触前终扣释放神经递质的空间组织和功能调节。我们以前的研究表明，活动诱导的CAZ重塑涉及从头合成以及泛素-蛋白酶体系统（UPS-）依赖的CAZ蛋白降解。本项目旨在研究控制CAZ的这种UPS依赖性调节的细胞和分子机制及其在活动诱导的突触前可塑性中的作用。为此，将研究CAZ蛋白巴松和liprin-β-内酰胺酶与泛素结合E3酶和蛋白酶体亚基的分子相互作用。我们将研究这些相互作用在调节UPS依赖的靶蛋白降解和连续的突触前功能的调制中的作用。此外，我们计划进行成像研究的活动依赖性调制的蛋白酶体的动态定位和持续性的轴突和突触前终扣。这项研究将获得新的见解UPS依赖性机制的活动依赖性重塑的CAZ在经验诱导和稳态突触可塑性。

项目成果

Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation

• DOI: 10.1038/emboj.2013.27
• 发表时间: 2013-04
• 期刊: The EMBO Journal
• 作者: C. Waites;Sergio A. Leal-Ortiz;Nathan D. Okerlund;Hannah Dalke;Anna Fejtová;W. Altrock;E. Gundelfinger;C. Garner

Synaptic activity controls localization and function of CtBP1 via binding to Bassoon and Piccolo

• DOI: 10.15252/embj.201488796
• 发表时间: 2015-04-15
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Ivanova, Daniela;Dirks, Anika;Fejtova, Anna
• 通讯作者: Fejtova, Anna