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Published on: February 25, 2014
Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of
Denise M Smith1,2,3, Michael L Niehoff1,4, Karen Ling5
1Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
Abstract:
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 GrnR493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in GrnR493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased GrnR493X 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 GrnR493X 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.
Insights
Nonsense mutations in the progranulin gene cause frontotemporal dementia (FTD). Inhibiting RNA decay pathways did not increase progranulin levels in mouse models, suggesting alternative strategies are needed for FTD treatment.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Nonsense mutations in the progranulin (GRN) gene are a common cause of frontotemporal dementia (FTD).
- Nonsense mutations trigger the nonsense-mediated RNA decay (NMD) pathway, reducing progranulin protein levels.
- Increasing progranulin levels is a potential therapeutic strategy for FTD.
Purpose of the Study:
- To investigate whether inhibiting the NMD pathway can increase progranulin levels in a mouse model of GRN-mutation-associated FTD.
- To evaluate the efficacy of antisense oligonucleotides (ASOs) and genetic deletion of UPF3b in upregulating progranulin.
Main Methods:
- Utilized a knock-in mouse model (GrnR493X) harboring a common patient mutation in the GRN gene.
- Administered antisense oligonucleotides (ASOs) targeting GRN mRNA to inhibit NMD.
- Assessed the impact of UPF3b gene deletion on NMD and progranulin levels.
Main Results:
- ASOs targeting GRN mRNA did not increase progranulin mRNA levels in the brains of GrnR493X mice, despite successful delivery and efficacy in other contexts.
- Genetic deletion of UPF3b, an NMD factor, perturbed NMD but failed to elevate Grn mRNA levels in the mouse model.
- These findings indicate that the tested NMD inhibition strategies were ineffective in this FTD mouse model.
Conclusions:
- Pharmacological and genetic inhibition of NMD are unlikely to be viable therapeutic approaches for increasing progranulin levels in FTD patients with GRN nonsense mutations.
- Alternative strategies targeting progranulin restoration should be explored for the treatment of GRN-associated FTD.
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