German Center for Neurodegenerative Diseases e.V. (DZNE), Charité Medical University, Berlin, Germany.
Center for Cancer Biomedicine, University of Oslo, Norwegian Radium Hospital, Oslo, Norway.
Elife. 2019 May 10;8:e46629. doi: 10.7554/eLife.46629.
Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders.
最近，活性区蛋白 Piccolo 的功能丧失与一种疾病有关，即 3 型桥小脑发育不良，该疾病会导致脑萎缩。在这里，我们探讨了 Piccolo 在大鼠神经元中的失活如何对突触功能产生不利影响，从而可能导致神经元丢失。我们的分析表明 Piccolo 对突触囊泡的再循环和维持至关重要。我们发现，缺乏 Piccolo 的突触点在 Rab5/EEA1 依赖性早期内体形成以及 SVs 的再循环方面存在缺陷。从机制上讲，Pra1 的突触募集减少导致 Rab5 功能受损，Pra1 已知选择性地与 Piccolo 的锌指结构域相互作用。重要的是，GTPase 缺陷型 Rab5 或 Piccolo 的 Znf1 结构域的过表达可恢复 SV 池的大小和再循环。这些数据提供了活性区与突触处内体分拣之间的分子联系，提示 Piccolo 如何导致发育和精神障碍。
