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Aged Monkey Brains Reveal the Role of Ubiquitin-Conjugating Enzyme UBE2N in the Synaptosomal Accumulation of Mutant Huntingtin
Yin P,Tu Z,Yin A,Zhao T,Yan S,Guo X,Chang R,Zhang L,Hong Y,Huang X,Zhou J,Wang Y,Li S,Li XJ
Hum Mol Genet
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.
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论文编号: |
DOI:10.1093/hmg/ddu544 |
论文题目: |
Aged Monkey Brains Reveal the Role of Ubiquitin-Conjugating Enzyme UBE2N in the Synaptosomal Accumulation of Mutant Huntingtin |
英文论文题目: |
Aged Monkey Brains Reveal the Role of Ubiquitin-Conjugating Enzyme UBE2N in the Synaptosomal Accumulation of Mutant Huntingtin |
第一作者: |
Yin P,Tu Z,Yin A,Zhao T,Yan S,Guo X,Chang R,Zhang L,Hong Y,Huang X,Zhou J,Wang Y,Li S,Li XJ |
英文第一作者: |
Yin P,Tu Z,Yin A,Zhao T,Yan S,Guo X,Chang R,Zhang L,Hong Y,Huang X,Zhou J,Wang Y,Li S,Li XJ |
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2014-10-27 |
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摘要: |
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. |
英文摘要: |
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. |
刊物名称: |
Hum Mol Genet |
英文刊物名称: |
Hum Mol Genet |
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其它备注: |
Yin P,Tu Z,Yin A,Zhao T,Yan S,Guo X,Chang R,Zhang L,Hong Y,Huang X,Zhou J,Wang Y,Li S,Li XJ. Aged Monkey Brains Reveal the Role of Ubiquitin-Conjugating Enzyme UBE2N in the Synaptosomal Accumulation of Mutant Huntingtin. Hum Mol Genet. DOI:10.1093/hmg/ddu544 |
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