Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

Johnson, Jennifer L.; Stoica, Loredana Elena; Liu, Yuwei; Zhu, Ping; Bhattacharya, Abhisek; Buffington, Shelly A.; Huq, Redwan; Eissa, N. Tony; Larsson, Ola; Porse, Bo T.; Domingo, Deepti; Nawaz, Urwah; Carroll, Renée; Jolly, Lachlan A.; Scerri, Tom S.; Kim, Hyung Goo; Brignell, Amanda; Coleman, Matthew; Braden, Ruth; Kini, Usha; Jackson, Victoria E.; Baxter, Anne; Bahlo, Melanie; Scheffer, Ingrid E.; Amor, David J.; Hildebrand, Michael S.; Bonnen, Penelope E.; Beeton, Christine; Gécz, Jozef; Morgan, Angela; Costa-Mattioli, Mauro

doi:10.1016/j.neuron.2019.08.027

Cited by 51 publications

(41 citation statements)

References 77 publications

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“…Since many NMD factors including UPF1 are conserved in all eukaryotes and required for survival in most metazoans [42][43][44] , chronic NMD inhibition would likely be detrimental to neuronal viability 13 . Indeed, loss-of-function mutations in both UPF2 and UPF3B have associated with intellectual disabilities 15,45 , suggesting a heightened vulnerability of the nervous system to NMD deficiencies.…”

Section: Discussionmentioning

confidence: 99%

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

et al. 2020

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Expansion of an intronic (GGGGCC) n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

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Section: Discussionmentioning

confidence: 99%

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

et al. 2020

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“…NMD has been shown to play an important role in neurological development and function in humans (Tarpey et al, 2007;Nguyen et al, 2013;Jaffrey and Wilkinson, 2018) and in mice (Bokhari et al, 2018;Johnson et al, 2019). However, the mouse models that have been used to examine the neurological aberrations that arise during NMD inhibition, including a Upf3b-null mouse (Huang et al, 2018) and a conditional null mouse that lacks Upf2 expression in the forebrain (Johnson et al, 2019), constitutively inhibit NMD during prenatal development. Thus, it has been unclear whether neurological dysfunction can be prevented if NMD is inhibited only after neonatal development.…”

Section: Discussionmentioning

confidence: 99%

A regulated NMD mouse model supports NMD inhibition as a viable therapeutic option to treat genetic diseases

Echols

Siddiqui

Dai

et al. 2020

Disease Models &Amp; Mechanisms

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Nonsense-mediated mRNA decay (NMD) targets mRNAs that contain a premature termination codon (PTC) for degradation, preventing their translation. By altering the expression of PTC-containing mRNAs, NMD modulates the inheritance pattern and severity of genetic diseases. NMD also limits the efficiency of suppressing translation termination at PTCs, an emerging therapeutic approach to treat genetic diseases caused by in-frame PTCs (nonsense mutations). Inhibiting NMD may help rescue partial levels of protein expression. However, it is unclear whether long-term, global NMD attenuation is safe. We hypothesize that a degree of NMD inhibition can be safely tolerated after completion of prenatal development. To test this hypothesis, we generated a novel transgenic mouse that expresses an inducible, dominant-negative form of human UPF1 (dnUPF1) to inhibit NMD in mouse tissues by different degrees, allowing us to examine the effects of global NMD inhibition in vivo. A thorough characterization of these mice indicated that expressing dnUPF1 at levels that promote relatively moderate to strong NMD inhibition in most tissues for a 1-month period produced modest immunological and bone alterations. In contrast, 1 month of dnUPF1 expression to promote more modest NMD inhibition in most tissues did not produce any discernable defects, indicating that moderate global NMD attenuation is generally well tolerated in non-neurological somatic tissues. Importantly, a modest level of NMD inhibition that produced no overt abnormalities was able to significantly enhance in vivo PTC suppression. These results suggest that safe levels of NMD attenuation are likely achievable, and this can help rescue protein deficiencies resulting from PTCs.

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“…Likewise, a UPF3B-independent NMD branch was described in human and mouse cells [ 62 , 153 ]. Both pathways are partially redundant in EJC-independent NMD, depend on UPF1 and SMG1 [ 154 ], and appear to have important functions in neural cell and brain metabolism, in embryonal development and in spermatogenesis [ 155 , 156 , 157 ].…”

Section: Are There Any Indispensable Trans -Acmentioning

confidence: 99%

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

Lavysh

Neu‐Yilik

2020

Biomolecules

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Nonsense-mediated RNA decay (NMD) is the prototype example of a whole family of RNA decay pathways that unfold around a common central effector protein called UPF1. While NMD in yeast appears to be a linear pathway, NMD in higher eukaryotes is a multifaceted phenomenon with high variability with respect to substrate RNAs, degradation efficiency, effector proteins and decay-triggering RNA features. Despite increasing knowledge of the mechanistic details, it seems ever more difficult to define NMD and to clearly distinguish it from a growing list of other UPF1-mediated RNA decay pathways (UMDs). With a focus on mammalian NMD, we here critically examine the prevailing NMD models and the gaps and inconsistencies in these models. By exploring the minimal requirements for NMD and other UMDs, we try to elucidate whether they are separate and definable pathways, or rather variations of the same phenomenon. Finally, we suggest that the operating principle of the UPF1-mediated decay family could be considered similar to that of a computing cloud providing a flexible infrastructure with rapid elasticity and dynamic access according to specific user needs.

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Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

Cited by 51 publications

References 77 publications

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

A regulated NMD mouse model supports NMD inhibition as a viable therapeutic option to treat genetic diseases

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

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