YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer’s disease  

作　　者：Jinfeng Sun Fan Chen Lingyu She Yuqing Zeng Hao Tang Bozhi Ye Wenhua Zheng Li Xiong Liwei Li Luyao Li Qin Yu Linjie Chen Wei Wang Guang Liang Xia Zhao 

机构地区：[1]Department of Pharmacy and Institute of Inflammation,Zhejiang Provincial People’s Hospital,Affiliated People’s Hospital,Hangzhou Medical College,Hangzhou 310014,China [2]Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products,School of Pharmacy,Hangzhou Medical College,Hangzhou 311399,China [3]Key Laboratory of Natural Medicines of the Changbai Mountain,Ministry of Education,Yanbian University,Yanji 133002,China [4]Affiliated Yongkang First People’s Hospital,Hangzhou Medical College,Yongkang 321399,China [5]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China [6]Center of Reproduction,Development and Aging and Institute of Translation Medicine,Faculty of Health Sciences,University of Macao,Taipa 999078,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期331-348,共18页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(21961142009 to Guang Liang and 82360805 to Jinfeng Sun);Zhejiang Provincial Key Scientific Project(2021C03041 to Guang Liang);Natural Science Foundation of Zhejiang province(LQ23H090018 to Xia Zhao);Medical and health Science and Technology Project of Zhejiang Province(2024KY055 to Xia Zhao).

摘　　要：Alzheimer’s disease(AD)is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation.In AD,sustained microglial activation triggers impaired synaptic pruning,neuroinflammation,neurotoxicity,and cognitive deficits.Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function.Here,we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology.Further study showed that YOD1 knockout significantly improved the migration,phagocytosis,and inflammatory response of microglia,thereby improving the cognitive impairment of AD model mice.Through LCeMS/MS analysis combined with Co-IP,we found that Myosin heavy chain 9(MYH9),a key regulator maintaining microglia homeostasis,is an interacting protein of YOD1.Mechanistically,YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9,thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis.Taken together,our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology,which provides a potential strategy for targeting microglia to treat AD.

关 键 词：Alzheimer's disease YOD1 Myosin heavy chain 9 MICROGLIA Inflammation Cognitivedysfunction 

分 类 号：R74[医药卫生—神经病学与精神病学]