A neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila
A neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila
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DOI：
10.1007/s00018-023-04778-9
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发表时间：
2023-05-01
影响因子：
8
通讯作者：
Zhang，Wei
中科院分区：
文献类型：
--
作者：
Li，Huifang;Yu，Zhenghong;Zhang，Wei
Ufmylation 是最近发现的一种小型泛素样修饰，其生物学功能和相关细胞靶点尚不清楚。在这里，我们提供了 Ufmylation 在果蝇衰老过程中涉及自噬相关基因 9 (Atg9) 的神经保护作用的证据。 Ufm1 系统通过 Atg9 协调自噬和 mTORC1，并维持线粒体稳态和 JNK（c-Jun N 末端激酶）活性，确保衰老神经元的健康。 Atg9 的神经元特异性表达可抑制因 Ufmylation 缺失而导致的与年龄相关的运动缺陷和死亡。此外，Atg9 被确定为由 Ddrgk1（Ufmylation 的关键调节因子）介导的 Ufm1 缀合的保守靶标。哺乳动物 Ddrgk1 被证明对于小鼠胚胎成纤维细胞 (MEF) 细胞中内源 Atg9A 蛋白的稳定性是不可或缺的。总而言之，我们的发现可能对哺乳动物的神经退行性疾病具有重要意义。
Ufmylation is a recently identified small ubiquitin-like modification, whose biological function and relevant cellular targets are poorly understood. Here we present evidence of a neuroprotective role for Ufmylation involving Autophagy-related gene 9 (Atg9) duringDrosophilaaging. The Ufm1 system ensures the health of aged neurons via Atg9 by coordinating autophagy and mTORC1, and maintaining mitochondrial homeostasis and JNK (c-Jun N-terminal kinase) activity. Neuron-specific expression of Atg9 suppresses the age-associated movement defect and lethality caused by loss of Ufmylation. Furthermore, Atg9 is identified as a conserved target of Ufm1 conjugation mediated by Ddrgk1, a critical regulator of Ufmylation. Mammalian Ddrgk1 was shown to be indispensable for the stability of endogenous Atg9A protein in mouse embryonic fibroblast (MEF) cells. Taken together, our findings might have important implications for neurodegenerative diseases in mammals.