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

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. •UBQLN2 is recruited to reduce poly-GA aggregation and alleviate its neurotoxicity•UBQLN2 can recognize HSP70 ubiquitination to facilitate poly-GA degradation•The UBQLN2-HSP70 interaction is required for poly-GA degradation•Pharmacologically enhancing HSP70 mitigates behavioral defects in poly-GA mice Dipeptide repeat proteins from GGGGCC expansion in the C9ORF72 gene contribute to ALS/FTD pathogenesis. Zhang et al. report that UBQLN2, another ALS/FTD risk factor, can recognize HSP70 ubiquitination to facilitate the clearance of poly-Gly-Ala aggregates, thereby alleviating poly-GA-induced neurotoxicity. Targeting the UBQLN2-HSP70 axis could be a promising strategy to treat C9ORF72-ALS/FTD.