日本东京大学Kazuo Emoto团队近期取得重要工作进展，他们研究发现，突触前Ube3a E3连接酶通过下调BMP信号传导促进突触的消除。相关研究成果2023年9月15日在线发表于《科学》杂志上。

据介绍，泛素连接酶Ube3a失活会导致发育障碍安吉尔曼综合症（一种罕见的神经发育障碍，表现为智力障碍、运动协调障碍、特殊的面部表情和行为特征等），而Ube3a剂量增加与自闭症谱系障碍相关。尽管Ube3a在轴突末端（包括突触前）的定位丰富，但人们对Ube3a的突触前功能及其突触前定位的机制知之甚少。

研究人员发现果蝇发育过程中的突触消除需要突触前Ube3a活性神经元。研究人员进一步鉴定了Ube3a与驱动蛋白马达相互作的结构域。相互作用结构域中与安吉尔曼综合症综合征相关的错义突变削弱了Ube3a的突触前靶向，并阻碍了突触的消除。相反，突触前Ube3a活性增加会导致突触过早消除并损害突触传递。

总之，这一研究揭示了Ube3a的生理作用，并提出了与Ube3a失调相关的潜在致病机制。

附：英文全文

Title: Presynaptic Ube3a E3 ligase promotes synapse elimination through down-regulation of BMP signaling

Author: Kotaro Furusawa, Kenichi Ishii, Masato Tsuji, Nagomi Tokumitsu, Eri Hasegawa, Kazuo Emoto

Issue&Volume: 2023-09-15

Abstract: Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in Drosophila neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome–associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.

DOI: ade8978

Source: https://www.science.org/doi/10.1126/science.ade8978