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

Sun, Yu; Eshov, Aziz; Zhou, Jeffrey; Isiktas, Atagun U.; Guo, Junjie U.

doi:10.1038/s41467-020-17129-0

Cited by 49 publications

(77 citation statements)

References 49 publications

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“…Recent studies have demonstrated that UPF1 expression can modulate DPR- or HRE-induced degenerative phenotypes in various OE models of C9-ALS ( Ortega et al, 2020 ; Sun et al, 2020 ; Xu et al, 2019 ). To validate this, we utilized a Drosophila melanogaster model of C9orf72 ALS that expresses 30 G 4 C 2 repeats (30R) upstream of a polyadenylation signal ( Xu et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…Dysfunction of multiple RNA metabolism pathways has been observed as a result of the HRE. Recently, three groups have published apparently discordant findings that nonsense-mediated decay (NMD) is either inhibited ( Sun et al, 2020 ; Xu et al, 2019 ) or upregulated ( Ortega et al, 2020 ) in different C9-ALS model systems.…”

Section: Introductionmentioning

confidence: 99%

“…NMD is an important, translation-dependent process to prevent the accumulation of truncated peptides that may adopt dominant-negative or other deleterious functions. The most recent, and perhaps most direct, investigation of NMD function in a C9-ALS model identifies that the apparent decrease in NMD function in the context of high poly(PR) concentrations is entirely accounted for by a reduction in translation, not a direct inhibition of NMD ( Sun et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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SUMMARY Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (G 4 C 2 ) 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 without altering the amount of repeat RNA, providing a potential mechanism by which UPF1 reduces dipeptide repeat (DPR) protein-mediated toxicity. Together, these findings indicate that UPF1 is neuroprotective in the context of C9-ALS, albeit independent of known UPF1-mediated NMD pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Nevertheless, our understanding of DPR-related toxicity has been augmented through the use of codon-optimized constructs expressing each DPR independent of G 4 C 2 repeats ( May et al, 2014 ; Mizielinska et al, 2014 ; Jovicic et al, 2015 ). Although poly-GA is the most abundant DPR localizing in p62-positive inclusions in postmortem tissues from C9ORF72 ALS/FTD patients, multiple lines of evidence suggest that arginine-rich DPRs are the most toxic of the five DPRs in both in vitro and in vivo disease models ( May et al, 2014 ; Mizielinska et al, 2014 ; Moens et al, 2019 ; Cook et al, 2020 ; Sun et al, 2020 ).…”

Section: Dprs the Gain Of Toxic Function: Clues From Different Modelmentioning

confidence: 99%

Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

Schmitz

Marques

Oertig

et al. 2021

Front. Cell. Neurosci.

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The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.

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“…Similarly, overexpression of GFP-GR 100 in HEK293T cells induced the formation of stress granules and delayed their disassembly as compared to HEK293T cells overexpressing GFP alone (Zhang et al, 2018 ). A recent study demonstrated that expression of polyGR and polyPR in transfected HeLa cells induced stress granule formation, with polyGR and polyPR expression causing stress granules to form in 45% of cells and 24% of cells, respectively (Sun et al, 2020 ).…”

Section: Effects Of Methylating Arginine On Membraneless Organellesmentioning

confidence: 99%

Hypothesis and Theory: Roles of Arginine Methylation in C9orf72-Mediated ALS and FTD

Gill

Premasiri

Vieira

2021

Front. Cell. Neurosci.

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Hexanucleotide repeat expansion (G4C2n) mutations in the gene C9ORF72 account for approximately 30% of familial cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as approximately 7% of sporadic cases of ALS. G4C2n mutations are known to result in the production of five species of dipeptide repeat proteins (DRPs) through non-canonical translation processes. Arginine-enriched dipeptide repeat proteins, glycine-arginine (polyGR), and proline-arginine (polyPR) have been demonstrated to be cytotoxic and deleterious in multiple experimental systems. Recently, we and others have implicated methylation of polyGR/polyPR arginine residues in disease processes related to G4C2n mutation-mediated neurodegeneration. We previously reported that inhibition of asymmetric dimethylation (ADMe) of arginine residues is protective in cell-based models of polyGR/polyPR cytotoxicity. These results are consistent with the idea that PRMT-mediated arginine methylation in the context of polyGR/polyPR exposure is harmful. However, it remains unclear why. Here we discuss the influence of arginine methylation on diverse cellular processes including liquid-liquid phase separation, chromatin remodeling, transcription, RNA processing, and RNA-binding protein localization, and we consider how methylation of polyGR/polyPR may disrupt processes essential for normal cellular function and survival.

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

Cited by 49 publications

References 49 publications

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

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

Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

Hypothesis and Theory: Roles of Arginine Methylation in C9orf72-Mediated ALS and FTD

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