UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction.

ABSTRACT: Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (G₄C₂) hexanucleotide repeat expansion (HRE), including aspects of RNA regulation such as nonsense-mediated decay (NMD). Here, we investigate the role that overexpression of UPF1, a protein involved in NMD, plays in mitigating neurotoxicity in multiple models of C9orf72 ALS/FTD. First, we show that NMD is not altered in our endogenous induced pluripotent stem cell (iPSC)-derived spinal neuron (iPSN) model of C9orf72 ALS (C9-ALS) or postmortem motor cortex tissue from C9-ALS patients. Unexpectedly, we find that UPF1 overexpression significantly reduces the severity of known neurodegenerative phenotypes without altering NMD function itself. UPF1 overexpression reduces poly(GP) abundance w

SUBMITTER: Zaepfel BL 

PROVIDER: S-EPMC8063722 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature