Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn ^R493X mouse model of frontotemporal dementia

by Denise M. Smith, Michael L. Niehoff, Karen Ling, Paymaan Jafar-Nejad, Frank Rigo, Susan A. Farr, Miles F. Wilkinson, Andrew D. Nguyen

A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin (GRN) gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these Grn^R493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in Grn^R493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased Grn^R493X mRNA levels in fibroblasts in vitro. However, following CNS delivery, we found that none of the 8 ASOs we tested increased Grn mRNA levels in the brains of Grn^R493X mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while Upf3b deletion effectively perturbed NMD, it did not increase Grn mRNA levels in Grn^+/R493X mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense GRN mutations. Thus, alternative approaches should be pursued.