Journal Article Research Support, Non-U.S. Gov't Ppublish
PubMed: 39807990 DOI: 10.1080/17590914.2024.2443442
New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia.
ASN Neuro 17(1):2443442
Authors: Linfang Wang, Shuanglong Yi, Shiping Zhang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Margaret S Ho
Affiliations
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China. The Institute of Seed Industry, Xianghu Laboratory, Qiantang River International Innovation Belt of the Xiaoshan Economic and Technological Development Zone, Hangzhou, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, China.
- Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China. The Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Abstract
We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a Drosophila PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.
MeSH
Autophagy, Neuroglia, Autophagosomes, Neurosciences