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Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Significance Amyotrophic lateral sclerosis (ALS) is a devastating disorder inevitably resulting in paralysis and death. Mutations in genes encoding RNA binding proteins cause familial ALS, but wild-type (WT) versions of these proteins accumulate in sporadic disease. In this study, we identified and characterized human up-frameshift protein 1 (hUPF1) as a potent modifier of neurodegeneration in ALS models. hUPF1 dramatically reduced toxicity in primary mammalian neurons expressing WT and disease-associated mutant RNA binding proteins, demonstrating efficacy in familial and sporadic disease models, and verifying the existence of a conserved neurotoxic pathway targeted by hUPF1. The work has fundamental implications for ALS disease mechanisms and offers a novel perspective on effective therapies generalizable to both sporadic and familial disease. Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.