title: Aged monkey brains reveal the role of ubiquitin-conjugating enzyme UBE2N in the synaptosomal accumulation of mutant huntingtin.
abstract: Although misfolded proteins are ubiquitinated and cleared by the proteasome, they can accumulate in synapses in aged neurons to promote synaptic dysfunction in a variety of neurodegenerative diseases, including Huntington's disease (HD), which is caused by polyglutamine expansion in huntingtin. The mechanism behind this aging-related phenomenon is unknown and has been difficult to investigate using animals with short life spans. With brain tissues from longer-lived rhesus monkeys of different ages, we found that aging reduces ubiquitin-proteasomal activity and also increases the level of ubiquitin-conjugating enzyme UBE2N (Ubc13) in synaptosomes. Synaptosomal fractions from aged monkey brain increase in vitro ubiquitinated huntingtin, whereas depletion of UBE2N markedly reduces this increase. Overexpressing UBE2N increases the aggregation of mutant huntingtin, and reducing UBE2N attenuates huntingtin aggregation in cellular and mouse models of HD. Our studies suggest that increased UBE2N plays a critical role in the synaptosomal accumulation of mutant huntingtin with age.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Zhuchi
authors.initials: Z
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: An
authors.initials: A
authors.lastname: Yin
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 347, Atlanta, GA 30322, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 347, Atlanta, GA 30322, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Renbao
authors.initials: R
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Lianhe
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 347, Atlanta, GA 30322, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Xiahe
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 347, Atlanta, GA 30322, USA.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing 100101, China Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 347, Atlanta, GA 30322, USA xli2@emory.edu.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics*; D008253:Macaca mulatta / Q000235:genetics; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D013574:Synaptosomes / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex