期刊
NEURON
卷 109, 期 12, 页码 1949-1962出版社
CELL PRESS
DOI: 10.1016/j.neuron.2021.04.023
关键词
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资金
- National Key Research and Development Program of China [2017YFA0104903, 2016YFA0501902, 2018YFA0107903]
- National Natural Science Foundation of China [31671040, 31871203, 32071032, 31701036]
- Zhejiang Provincial Natural Science Foundation of China [LR17H090001]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
UBQLN2 plays a critical role in reducing poly-GA aggregates and alleviating poly-GA-induced neurotoxicity in C9-ALS/FTD by recognizing HSP70 ubiquitination and promoting poly-GA degradation. Disruption of the interaction between UBQLN2 and HSP70 inhibits poly-GA aggregation in C9ALS/FTD iPSC-derived neurons. Enhancing HSP70 with the chemical compound 17AAG at the adult stage mitigates behavioral defects in poly-GA animals.
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 C9ALS/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 UBQLN2HSP70 axis in protein aggregate clearance in C9-ALS/FTD.
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