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UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model.
Zhang, Kejing; Wang, Ailian; Zhong, Keke; Qi, Shuyuan; Wei, Chen; Shu, Xiaoqiu; Tu, Wen-Yo; Xu, Wentao; Xia, Congcong; Xiao, Yatao; Chen, Aizhong; Bai, Lei; Zhang, Jianmin; Luo, Benyan; Wang, Wenyuan; Shen, Chengyong.
Affiliation
  • Zhang K; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Wang A; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Zhong K; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Qi S; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Wei C; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Shu X; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Tu WY; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Xu W; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Xia C; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • Xiao Y; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Chen A; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Bai L; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Zhang J; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Luo B; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
  • Wang W; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: wywang@sioc.ac.cn.
  • Shen C; Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China; Department of Neurobiology, Key Laboratory of Medical Neurobiology of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang
Neuron ; 109(12): 1949-1962.e6, 2021 06 16.
Article in En | MEDLINE | ID: mdl-33991504
ABSTRACT
Expansion of a hexanucleotide repeat GGGGCC (G4C2) in the intron of the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Transcripts carrying G4C2 repeat expansions generate neurotoxic dipeptide repeat (DPR) proteins, including poly-Gly-Ala (poly-GA), which tends to form protein aggregates. Here, we demonstrate that UBQLN2, another ALS/FTD risk factor, is recruited to reduce poly-GA aggregates and alleviate poly-GA-induced neurotoxicity. UBQLN2 could recognize HSP70 ubiquitination, which facilitates the UBQLN2-HSP70-GA complex formation and promotes poly-GA degradation. ALS/FTD-related UBQLN2 mutants fail to bind HSP70 and clear poly-GA aggregates. Disruption of the interaction between UBQLN2 and HSP70 inhibits poly-GA aggregation in C9-ALS/FTD iPSC-derived neurons. Finally, enhancing HSP70 by the chemical compound 17AAG at the adult stage mitigates behavioral defects in poly-GA animals. Our findings suggest a critical role of the UBQLN2-HSP70 axis in protein aggregate clearance in C9-ALS/FTD.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HSP70 Heat-Shock Proteins / Adaptor Proteins, Signal Transducing / Frontotemporal Dementia / Autophagy-Related Proteins / C9orf72 Protein / Amyotrophic Lateral Sclerosis Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Document type: Article Affiliation country: China
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HSP70 Heat-Shock Proteins / Adaptor Proteins, Signal Transducing / Frontotemporal Dementia / Autophagy-Related Proteins / C9orf72 Protein / Amyotrophic Lateral Sclerosis Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Document type: Article Affiliation country: China