Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology  

作　　者：Yiyang Qin Wenzhen Zhu Tingting Guo Yiran Zhang Tingting Xing Peng Yin Shihua Li Xiao-Jiang Li Su Yang 

机构地区：[1]Guangdong Key Laboratory of Non-human Primate Research,Key Laboratory of CNS Regeneration(Ministry of Education),Guangdong–HongKong–Macao Institute of CNS Regeneration,Jinan University,Guangzhou,Guangdong Province,China

出　　处：《Neural Regeneration Research》2025年第9期2655-2666,共12页中国神经再生研究（英文版）

基　　金：supported by the National Key R&D Program of China,No.2021YFA0805200(to SY);the National Natural Science Foundation of China,No.31970954(to SY);two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。

摘　　要：Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

关 键 词：androgen receptor mesencephalic astrocyte-derived neurotrophic factor mouse model NEURODEGENERATION neuronal loss neurotrophic factor polyglutamine disease protein misfolding spinal and bulbar muscular atrophy transcription factor 

分 类 号：R741[医药卫生—神经病学与精神病学]