Lützkendorf J, Matkovic-Rachid T, Liu S, Götz T, Gao L, Turrel O, Maglione M, Grieger M, Putignano S, Ramesh N, Ghelani T, Neumann A, Gimber N, Schmoranzer J, Stawrakakis A, Brence B, Baum D, Ludwig Kai, Heine M, Mielke T, Liu F, Walter A M, Wahl M C, Sigrist S J
Freie Universität Berlin, Institute for Biology and Genetics, Berlin, Germany.
Freie Universität Berlin, Institute of Chemistry and Biochemistry/Structural Biochemistry, Berlin, Germany.
Nat Commun. 2025 Jan 2;16(1):271. doi: 10.1038/s41467-024-55382-9.
At presynaptic active zones (AZs), scaffold proteins are critical for coordinating synaptic vesicle release and forming essential nanoarchitectures. However, regulatory principles steering AZ scaffold assembly, function, and plasticity remain insufficiently understood. We here identify an additional Drosophila AZ protein, "Blobby", essential for proper AZ nano-organization. Blobby biochemically associates with the ELKS family AZ scaffold protein Bruchpilot (BRP) and integrates into newly forming AZs. Loss of Blobby results in fewer AZs forming, ectopic AZ scaffold protein accumulations ("blobs") and disrupts nanoscale architecture of the BRP-AZ scaffold. Functionally, blobby mutants show diminished evoked synaptic currents due to reduced synaptic vesicle release probability and fewer functional release sites. Blobby is also present in adult brain synapses, and post-developmental knockdown of Blobby in the mushroom body impairs olfactory aversive memory consolidation. Thus, our analysis identifies an additional layer of AZ regulation critical for developmental AZ assembly but also for AZ-mediated plasticity controlling behavior.
在突触前活性区（AZs），支架蛋白对于协调突触小泡释放和形成基本的纳米结构至关重要。然而，指导AZ支架组装、功能和可塑性的调控原则仍未得到充分理解。我们在此鉴定出一种额外的果蝇AZ蛋白“Blob”，它对于正确的AZ纳米组织至关重要。Blob在生物化学上与ELKS家族的AZ支架蛋白布鲁赫普洛特（BRP）相关联，并整合到新形成的AZs中。Blob的缺失导致形成的AZs减少、异位的AZ支架蛋白积累（“斑点”），并破坏BRP - AZ支架的纳米级结构。在功能上，由于突触小泡释放概率降低和功能性释放位点减少，blob突变体表现出诱发的突触电流减弱。Blob也存在于成体脑突触中，在蘑菇体中发育后敲低Blob会损害嗅觉厌恶记忆巩固。因此，我们的分析确定了AZ调控的一个额外层面，这对于发育中的AZ组装以及控制行为的AZ介导的可塑性都至关重要。
