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The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates

文献类型：期刊论文

作者Pu, Mei6,7,8; Tai, Yusi6,8; Yuan, Luyang5; Zhang, Yu4; Guo, Huijie6,7,8; Hao, Zongbing2,3; Chen, Jing8; Qi, Xinming8; Wang, Guanghui2,3; Tao, Zhouteng1,8
刊名CELLULAR AND MOLECULAR LIFE SCIENCES
出版日期2022-09-01
卷号79期号:9页码:23
ISSN号1420-682X
关键词ALS C9orf72 Poly-GA Proteasome Autophagy
DOI10.1007/s00018-022-04518-5
通讯作者Wang, Guanghui(wanggh@suda.edu.cn) ; Tao, Zhouteng(taozhouteng@simm.ac.cn) ; Ren, Jin(jren@cdser.simm.ac.cn)
英文摘要Background Poly-GA, a dipeptide repeat protein unconventionally translated from GGGGCC (G4C2) repeat expansions in C9orf72, is abundant in C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9orf72-ALS/FTD). Although the poly-GA aggregates have been identified in C9orf72-ALS/FTD neurons, the effects on UPS (ubiquitin-proteasome system) and autophagy and their exact molecular mechanisms have not been fully elucidated. Results Herein, our in vivo experiments indicate that the mice expressing ploy-GA with 150 repeats instead of 30 repeats exhibit significant aggregates in cells. Mice expressing 150 repeats ploy-GA shows behavioral deficits and activates autophagy in the brain. In vitro findings suggest that the poly-GA aggregates influence proteasomal by directly binding proteasome subunit PSMD2. Subsequently, the poly-GA aggregates activate phosphorylation and ubiquitination of p62 to recruit autophagosomes. Ultimately, the poly-GA aggregates lead to compensatory activation of autophagy. In vivo studies further reveal that rapamycin (autophagy activator) treatment significantly improves the degenerative symptoms and alleviates neuronal injury in mice expressing 150 repeats poly-GA. Meanwhile, rapamycin administration to mice expressing 150 repeats poly-GA reduces neuroinflammation and aggregates in the brain. Conclusion In summary, we elucidate the relationship between poly-GA in the proteasome and autophagy: when poly-GA forms complexes with the proteasome, it recruits autophagosomes and affects proteasome function. Our study provides support for further promoting the comprehension of the pathogenesis of C9orf72, which may bring a hint for the exploration of rapamycin for the treatment of ALS/FTD.
WOS关键词REGULATES AGGRESOME FORMATION ; HEXANUCLEOTIDE REPEAT ; MOUSE MODEL ; DEGRADATION ; PROTEINS ; DISEASE ; NUCLEAR ; PHOSPHORYLATION ; INCLUSIONS ; CLEARANCE
资助项目Foundation of Shanghai Science and Technology Committee[21ZR1475100] ; Foundation of Shanghai Science and Technology Committee[21DZ2291100] ; Fundamental Research Funds for the State Key Laboratory of Drug Research[SIMM2103ZZ-01] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202210]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
出版者SPRINGER BASEL AG
WOS记录号WOS:000847364900001
源URL[http://119.78.100.183/handle/2S10ELR8/302141]  
专题新药研究国家重点实验室
通讯作者Wang, Guanghui; Tao, Zhouteng; Ren, Jin
作者单位1.Chinese Acad Sci, Xian Inst Opt & Precis Mech, State Key Lab Transient Opt & Photon, Xian, Peoples R China
2.Soochow Univ, Coll Pharmaceut Sci, Dept Pharmacol, Suzhou, Jiangsu, Peoples R China
3.Soochow Univ, Coll Pharmaceut Sci, Jiangsu Key Lab Neuropsychiat Dis, Lab Mol Neuropathol, Suzhou, Jiangsu, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Neuropharmacol, Key Lab Receptor Res, Shanghai, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
6.Univ Chinese Acad Sci, Beijing, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
8.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Pu, Mei,Tai, Yusi,Yuan, Luyang,et al. The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates[J]. CELLULAR AND MOLECULAR LIFE SCIENCES,2022,79(9):23.
APA Pu, Mei.,Tai, Yusi.,Yuan, Luyang.,Zhang, Yu.,Guo, Huijie.,...&Ren, Jin.(2022).The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates.CELLULAR AND MOLECULAR LIFE SCIENCES,79(9),23.
MLA Pu, Mei,et al."The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates".CELLULAR AND MOLECULAR LIFE SCIENCES 79.9(2022):23.

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来源：上海药物研究所

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