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γ-分泌酶通过切割 Wnt 受体促进果蝇突触后发育。

γ-secretase promotes Drosophila postsynaptic development through the cleavage of a Wnt receptor.

机构信息

Department of Neuroscience, Vickie and Jack Farber Institute of Neuroscience, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA 19107, USA.

Department of Neuroscience, Vickie and Jack Farber Institute of Neuroscience, Thomas Jefferson University, Bluemle Life Sciences Building, Philadelphia, PA 19107, USA.

出版信息

Dev Cell. 2022 Jul 11;57(13):1643-1660.e7. doi: 10.1016/j.devcel.2022.05.006. Epub 2022 Jun 1.

Abstract

Developing synapses mature through the recruitment of specific proteins that stabilize presynaptic and postsynaptic structure and function. Wnt ligands signaling via Frizzled (Fz) receptors play many crucial roles in neuronal and synaptic development, but whether and how Wnt and Fz influence synaptic maturation is incompletely understood. Here, we show that Fz2 receptor cleavage via the γ-secretase complex is required for postsynaptic development and maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to recruit postsynaptic scaffolding and cytoskeletal proteins, leading to behavioral deficits. Introducing presenilin mutations linked to familial early-onset Alzheimer's disease into flies leads to synaptic maturation phenotypes that are identical to those seen in null alleles. This conserved role for γ-secretase in synaptic maturation and postsynaptic development highlights the importance of Fz2 cleavage and suggests that receptor processing by proteins linked to neurodegeneration may be a shared mechanism with aspects of synaptic development.

摘要

形成中的突触通过募集特定的蛋白质而成熟,这些蛋白质可稳定突触前和突触后的结构和功能。通过 Frizzled(Fz)受体进行信号传递的 Wnt 配体在神经元和突触发育中发挥着许多关键作用,但 Wnt 和 Fz 是否以及如何影响突触成熟还不完全清楚。在这里,我们发现 Fz2 受体通过 γ-分泌酶复合物的切割对于突触后发育和成熟是必需的。在没有 γ-分泌酶的情况下,果蝇的神经肌肉突触无法募集突触后支架和细胞骨架蛋白,导致行为缺陷。将与家族性早发性阿尔茨海默病相关的早老素突变引入果蝇中,会导致与缺失突变体中观察到的相同的突触成熟表型。γ-分泌酶在突触成熟和突触后发育中的这种保守作用突出了 Fz2 切割的重要性,并表明与神经退行性疾病相关的蛋白质对受体的加工可能是与突触发育某些方面共享的机制。

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