UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model

Kejing Zhang; Ailian Wang; Keke Zhong; Shuyuan Qi; Chen Wei; Xiaoqiu Shu; Wen-Yo Tu; Wentao Xu; Congcong Xia; Yatao Xiao; Aizhong Chen; Lei Bai; Jianmin Zhang; Benyan Luo; Wenyuan Wang; Chengyong Shen

doi:10.1016/j.neuron.2021.04.023

UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model

Neuron. 2021 Jun 16;109(12):1949-1962.e6. doi: 10.1016/j.neuron.2021.04.023. Epub 2021 May 14.

Authors

Kejing Zhang¹, Ailian Wang¹, Keke Zhong¹, Shuyuan Qi¹, Chen Wei¹, Xiaoqiu Shu¹, Wen-Yo Tu¹, Wentao Xu¹, Congcong Xia², Yatao Xiao¹, Aizhong Chen¹, Lei Bai¹, Jianmin Zhang¹, Benyan Luo¹, Wenyuan Wang³, Chengyong Shen⁴

Affiliations

¹ Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
² 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.
³ 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.
⁴ 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 310020, China. Electronic address: cshen@zju.edu.cn.

PMID: 33991504
DOI: 10.1016/j.neuron.2021.04.023

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.

Keywords: C9orf72; HSP70; UBQLN2; amyotrophic lateral sclerosis; frontotemporal dementia; protein aggregation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / metabolism
Amyotrophic Lateral Sclerosis / pathology
Amyotrophic Lateral Sclerosis / physiopathology
Animals
Autophagy-Related Proteins / genetics*
Autophagy-Related Proteins / metabolism
C9orf72 Protein / genetics*
C9orf72 Protein / metabolism
DNA Repeat Expansion
Disease Models, Animal
Frontotemporal Dementia / genetics*
Frontotemporal Dementia / metabolism
Frontotemporal Dementia / pathology
Frontotemporal Dementia / physiopathology
HEK293 Cells
HSP70 Heat-Shock Proteins / genetics*
HSP70 Heat-Shock Proteins / metabolism
Humans
Induced Pluripotent Stem Cells
Mice
Motor Cortex / pathology
Polymers / metabolism
Protein Aggregation, Pathological / genetics
Protein Aggregation, Pathological / metabolism
Protein Aggregation, Pathological / pathology
Protein Aggregation, Pathological / physiopathology
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
C9orf72 Protein
HSP70 Heat-Shock Proteins
Polymers
UBQLN2 protein, human
UBQLN2 protein, mouse
poly(alanylglycine)