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A neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila

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Abstract

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) during Drosophila aging. 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.

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No new datasets were generated during the current study.

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Acknowledgements

We thank Dr. Tong Chao (Zhejiang University) for kindly providing UAS-GFP-Atg9 flies. We also thank Dr. Chen Guang-Chao (National Taiwan University) and Dr. Chen Yawen for providing pUAST-Flag-Atg9 plasmid. We thank Dr. Cai Yu (Temasek Life Sciences laboratory, Singapore) for pActin-Gal4 plasmid.

Funding

This work was supported by the National Natural Science Foundation of China (No. 31701229, 32270516 and 31970413), Senior Health Research Project of Jiangsu Provincial Health Commission (LKM2023010) and National Key R&D Program of China (2018YFC1200201).

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  1. Huifang Li, Zhenghong Yu, Zikang Niu, Yun Cheng and Zhenhao Wei have contributed equally to this work.

Authors and Affiliations

  1. College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China

    Huifang Li, Zikang Niu, Zhenhao Wei, Yafei Cai, Lanxin Hu, Jiejie Zhu & Wei Zhang

  2. Department of Rheumatology and Immunology, Jinling Hospital, Affiliated Hosptial of Medical School, Nanjing University, Nanjing, 210002, China

    Zhenghong Yu

  3. Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China

    Yun Cheng

  4. College of Life Science, Nanjing Normal University, Nanjing, 210023, China

    Fei Ma

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Contributions

WZ designed the experiments. HL, ZY, ZN, YC, ZW, LH and JZ performed the experiments. HL, ZY, ZN, YC, YC, FM and ZW analyzed the data. WZ, ZY and YC wrote the manuscript.

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Correspondence to Wei Zhang.

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Li, H., Yu, Z., Niu, Z. et al. A neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila. Cell. Mol. Life Sci. 80, 129 (2023). https://doi.org/10.1007/s00018-023-04778-9

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