UBQLN2 Promotes C9ORF72 Poly(GA) Protein Clearance In Amyotrophic Lateral Sclerosis

Accumulation of protein aggregates is a notorious feature in multiple of neurodegenerative disorders.Expansion of a hexanucleotide repeat GGGGCC(G4C2)in the intron of C90RF72 gene is the most common cause of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD).Transcripts carrying(G4C2)expansions undergo a non-ATG-dependent translation,generating neurotoxic dipeptide repeat(DPR)proteins and contributing to ALS/FTD.However,the prevalence of C9orf72-ALS/FTD is not 100%,suggesting that there are other mechanisms to regulate the disease.UBQLN2 is another ALS risk gene.Here,we found UBQLN2 is colocalized and interacted with GA aggregates,and UBQLN2 is sufficient and necessary for GA aggregates clearance in vitro.UBQLN2 recognizes UBR5-mediated GA aggregates ubiquitination and clears it through proteasome and autophagy.Part of the ALS mutations of UBQLN2 lost the ability in the GA aggregates clearance.Importantly,administration of exogenous UBQLN2 promoted GA aggregates degradation and rescued GA induced neuron degeneration and behavior defects in ALS/FTD animal models.Our findings suggest that the impairment of a common pathway in protein aggregates clearance in the pathogenesis of ALS/FTD.