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• W2917882620 abstract "One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. One drug, two diseases is a rare and economical therapeutic strategy that is highly desirable in the pharmaceutical industry. We previously reported a 21-amino acid peptide named beta-structured inhibitor for neurodegenerative diseases (BIND) that can effectively inhibit expanded CAG trinucleotide toxicity in polyglutamine (polyQ) diseases. Here we report that BIND also effectively inhibits GGGGCC repeat-mediated neurodegeneration in vitro and in vivo. When fused with a cell-penetrating peptide derived from the transactivator of transcription (TAT) protein of the HIV, TAT-BIND reduces cell death, formation of GGGGCC RNA foci, and levels of poly-GR, poly-GA, and poly-GP dipeptide proteins in cell models of C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS-FTD). We showed that TAT-BIND disrupts the interaction between GGGGCC RNA and nucleolin protein, restores rRNA maturation, and inhibits mislocalization of nucleolin and B23, which eventually suppresses nucleolar stress in C9ALS-FTD. In a Drosophila model of C9ALS-FTD, TAT-BIND suppresses retinal degeneration, rescues climbing ability, and extends the lifespan of flies. In contrast, TAT-BIND has no effect on UAS-poly-glycine-arginine (poly-GR)100-expressing flies, which generate only poly-GR protein toxicity, indicating BIND ameliorates toxicity in C9ALS-FTD models via a r(GGGGCC)exp-dependent inhibitory mechanism. Our findings demonstrated that, apart from being a potential therapeutic for polyQ diseases, BIND is also a potent peptidylic inhibitor that suppresses expanded GGGGCC RNA-mediated neurodegeneration, highlighting its potential application in C9ALS-FTD treatment. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective treatment. The hexanucleotide (HRE) GGGGCC repeat expansion in the non-coding region of the C9ORF72 gene has been reported to contribute to up to 40% of ALS and FTD cases.1DeJesus-Hernandez M. Mackenzie I.R. Boeve B.F. Boxer A.L. Baker M. Rutherford N.J. Nicholson A.M. Finch N.A. Flynn H. Adamson J. et al.Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.Neuron. 2011; 72: 245-256Abstract Full Text Full Text PDF PubMed Scopus (3410) Google Scholar, 2Renton A.E. Majounie E. Waite A. Simón-Sánchez J. Rollinson S. Gibbs J.R. Schymick J.C. Laaksovirta H. van Swieten J.C. 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Tan W. Westergard T. Krishnamurthy K. Markandaiah S.S. Shi Y. Lin S. Shneider N.A. Monaghan J. Pandey U.B. et al.Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.Neuron. 2014; 84: 1213-1225Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 13Zhang Y.J. Gendron T.F. Grima J.C. Sasaguri H. Jansen-West K. Xu Y.F. Katzman R.B. Gass J. Murray M.E. Shinohara M. et al.C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins.Nat. Neurosci. 2016; 19: 668-677Crossref PubMed Scopus (209) Google Scholar, 14Zhang Y.J. Jansen-West K. Xu Y.F. Gendron T.F. Bieniek K.F. Lin W.L. Sasaguri H. Caulfield T. Hubbard J. Daughrity L. et al.Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress.Acta Neuropathol. 2014; 128: 505-524Crossref PubMed Scopus (219) Google Scholar, 15Lee Y.B. Baskaran P. Gomez-Deza J. Chen H.J. Nishimura A.L. Smith B.N. Troakes C. Adachi Y. Stepto A. Petrucelli L. et al.C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity.Hum. Mol. Genet. 2017; 26: 4765-4777Crossref PubMed Scopus (46) Google Scholar while the arginine-containing poly-GR and poly-PR proteins are found to be particularly toxic.11Mizielinska S. Grönke S. Niccoli T. Ridler C.E. Clayton E.L. Devoy A. Moens T. Norona F.E. Woollacott I.O.C. Pietrzyk J. et al.C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.Science. 2014; 345: 1192-1194Crossref PubMed Scopus (452) Google Scholar, 12Wen X. Tan W. Westergard T. Krishnamurthy K. Markandaiah S.S. Shi Y. Lin S. Shneider N.A. Monaghan J. Pandey U.B. et al.Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.Neuron. 2014; 84: 1213-1225Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar Thus, GGGGCC repeat-containing RNAs and their respective protein products are both toxic species, and they both contribute to the pathogenesis of C9ALS-FTD. A pathogenic feature of C9ALS-FTD is the notable buildup of nucleolar stress in affected cells,16Haeusler A.R. Donnelly C.J. Periz G. Simko E.A. Shaw P.G. Kim M.S. Maragakis N.J. Troncoso J.C. Pandey A. Sattler R. et al.C9orf72 nucleotide repeat structures initiate molecular cascades of disease.Nature. 2014; 507: 195-200Crossref PubMed Scopus (624) Google Scholar, 17Tao Z. Wang H. Xia Q. Li K. Li K. Jiang X. Xu G. Wang G. Ying Z. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity.Hum. Mol. 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Nucleolar stress with and without p53.Nucleus. 2014; 5: 402-426Crossref PubMed Scopus (172) Google Scholar and eventually leads to apoptosis.25Wong C.H. Nguyen L. Peh J. Luu L.M. Sanchez J.S. Richardson S.L. Tuccinardi T. Tsoi H. Chan W.Y. Chan H.Y. et al.Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor.J. Am. Chem. Soc. 2014; 136: 6355-6361Crossref PubMed Scopus (75) Google Scholar Nucleolar stress is widely reported in neurodegenerative diseases, including polyglutamine (polyQ) diseases,26Chan H.Y. RNA-mediated pathogenic mechanisms in polyglutamine diseases and amyotrophic lateral sclerosis.Front. Cell. Neurosci. 2014; 8: 431Crossref PubMed Scopus (22) Google Scholar, 27Tsoi H. Chan H.Y. Expression of expanded CAG transcripts triggers nucleolar stress in Huntington’s disease.Cerebellum. 2013; 12: 310-312Crossref PubMed Scopus (53) Google Scholar, 28Tsoi H. Chan H.Y. Roles of the nucleolus in the CAG RNA-mediated toxicity.Biochim. 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Genet. 2015; 24: 2426-2441Crossref PubMed Scopus (162) Google Scholar The r(GGGGCC)exp has been reported to sequester nucleolin (NCL) proteins, obstruct the maturation of rRNA, and finally induce nucleolar stress.16Haeusler A.R. Donnelly C.J. Periz G. Simko E.A. Shaw P.G. Kim M.S. Maragakis N.J. Troncoso J.C. Pandey A. Sattler R. et al.C9orf72 nucleotide repeat structures initiate molecular cascades of disease.Nature. 2014; 507: 195-200Crossref PubMed Scopus (624) Google Scholar The poly-GR and poly-PR proteins have also been demonstrated to cause the translocation of the key nucleolar component nucleophosmin (B23) and NCL, leading to nucleolar stress and cell death.17Tao Z. Wang H. Xia Q. Li K. Li K. Jiang X. Xu G. Wang G. Ying Z. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity.Hum. Mol. Genet. 2015; 24: 2426-2441Crossref PubMed Scopus (162) Google Scholar We recently reported the activity of a therapeutic peptide inhibitor candidate against CAG RNA toxicity named beta-structured inhibitor for neurodegenerative diseases (BIND).34Zhang Q. Chen Z.S. An Y. Liu H. Hou Y. Li W. Lau K.F. Koon A.C. Ngo J.C.K. Chan H.Y.E. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases.RNA. 2018; 24: 486-498Crossref PubMed Scopus (17) Google Scholar The BIND sequence is derived from the RNA recognition motif (RRM) 2 of NCL protein. By fusing with the cell-penetrating peptide (CPP), a sequence derived from the transactivator of transcription (TAT) protein of HIV-1, to BIND, the TAT-BIND peptide was capable of inhibiting NCL-expanded CAG RNA interaction and suppressing nucleolar stress in polyQ diseases.34Zhang Q. Chen Z.S. An Y. Liu H. Hou Y. Li W. Lau K.F. Koon A.C. Ngo J.C.K. Chan H.Y.E. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases.RNA. 2018; 24: 486-498Crossref PubMed Scopus (17) Google Scholar Here we report that TAT-BIND, apart from being a potent suppressor of expanded CAG RNA toxicity, is also a potent suppressor of expanded GGGGCC RNA-mediated toxicity. TAT-BIND reduced GGGGCC-induced cell death, RNA foci formation, poly-GP, poly-GR, and poly-GA dipeptide protein levels, and nucleolar stress in cell models of C9ALS-FTD. When applied to in vivo disease models, TAT-BIND effectively suppressed neurodegeneration in a GGGGCC repeat length-dependent manner. Not only did our findings open up a new potential therapeutic treatment for C9ALS-FTD, our results also presented a rare and economical one drug, two diseases strategy that is highly desirable for further therapeutic development. The central region of the NCL protein contains four RRMs.35Ginisty H. Sicard H. Roger B. Bouvet P. Structure and functions of nucleolin.J. Cell Sci. 1999; 112: 761-772Crossref PubMed Google Scholar Based on sequence and structural analysis of the four individual RRMs, we predicted the potential RNA-binding region on each RRM, and we generated synthetic peptides derived from each of these regions in an attempt to identify sequences that could suppress r(GGGGCC)exp-mediated defects (Table 1). One of the peptides, RRM2-P1, has been designated previously as BIND, as it showed inhibitory activity against expanded CAG RNA-induced toxicity in our earlier work.34Zhang Q. Chen Z.S. An Y. Liu H. Hou Y. Li W. Lau K.F. Koon A.C. Ngo J.C.K. Chan H.Y.E. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases.RNA. 2018; 24: 486-498Crossref PubMed Scopus (17) Google Scholar To facilitate cellular uptake, we fused an 11-residue-long CPP (YGRKKRRQRRR) derived from residues 47–57 of the TAT protein from the HIV to the N termini of all the peptides.30Zhang Q. Tsoi H. Peng S. Li P.P. Lau K.F. Rudnicki D.D. Ngo J.C. Chan H.Y. Assessing a peptidylic inhibitor-based therapeutic approach that simultaneously suppresses polyglutamine RNA- and protein-mediated toxicities in patient cells and Drosophila.Dis. Model. Mech. 2016; 9: 321-334Crossref PubMed Scopus (15) Google Scholar, 34Zhang Q. Chen Z.S. An Y. Liu H. Hou Y. Li W. Lau K.F. Koon A.C. Ngo J.C.K. Chan H.Y.E. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases.RNA. 2018; 24: 486-498Crossref PubMed Scopus (17) Google Scholar, 36Frankel A.D. Pabo C.O. 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Cell-penetrating peptides: a comparative membrane toxicity study.Anal. Biochem. 2005; 345: 55-65Crossref PubMed Scopus (214) Google Scholar The pAG3-(GGGGCC)2/66 construct is a set of well-defined constructs; pAG3-(GGGGCC)66 expresses both expanded GGGGCC repeat RNA and RAN-translated DPR proteins.41Su Z. Zhang Y. Gendron T.F. Bauer P.O. Chew J. Yang W.Y. Fostvedt E. Jansen-West K. Belzil V.V. Desaro P. et al.Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS.Neuron. 2014; 84: 239Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 42Gendron T.F. Bieniek K.F. Zhang Y.J. Jansen-West K. Ash P.E. Caulfield T. Daughrity L. Dunmore J.H. Castanedes-Casey M. Chew J. et al.Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS.Acta Neuropathol. 2013; 126: 829-844Crossref PubMed Scopus (385) Google ScholarTable 1Sequence of TAT and the Respective NCL RRM-Derived PeptidePeptideSequenceDerived fromTATYGRKKRRQRRRHIV-1 virus transactivatorTAT-RRM1-P1YGRKKRRQRRRTGTNRKFGYVDRRM1 of NCLTAT-RRM2-P1YGRKKRRQRRRAEIRLVSKDGKSKGIAYIEFKRRM2 of NCLTAT-RRM3-P1YGRKKRRQRRRTFIKVPQNQNGKSKGYAFRRM3 of NCLTAT-RRM4-P1YGRKKRRQRRRRARIVTDRETGSSKGFGFVDRRM4 of NCL Open table in a new tab We employed the lactate dehydrogenase (LDH) assay to detect cell death in our cell model,43Bañez-Coronel M. Porta S. Kagerbauer B. Mateu-Huertas E. Pantano L. Ferrer I. Guzmán M. Estivill X. Martí E. A pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity.PLoS Genet. 2012; 8: e1002481Crossref PubMed Scopus (138) Google Scholar and we confirmed that (GGGGCC)66 expression caused significant cell death in SK-N-MC cells (Figures 1A–1D). Our results showed that the application of TAT-RRM2-P1, hereafter referred to as TAT-BIND, suppressed (GGGGCC)66-induced cell death in a dose-dependent manner (Figure 1B). The application of 1 μM TAT-BIND on cells suppressed approximately 25% of the relative cell death induced by (GGGGCC)66 expression, whereas the 10- and 20-μM treatments nearly completely suppressed cell death in our cell model (Figure 1B). On the other hand, a slight but significant suppression of cell death was observed when 0.1 or 1 μM TAT-RRM3-P1 was applied (Figure 1C). However, the suppressive effect of TAT-RRM3-P1 diminished when higher concentrations of peptide were used (Figure 1C). We suspect this might be the result of the peptide forming soluble aggregates due to its higher content of hydrogen bond donors and acceptors. Alternatively, it could be caused by toxicity induced by the TAT-RRM3-P1 peptide itself. Considering the significant dose-dependent inhibitory effect of TAT-BIND, we selected it for further investigation. To test the specificity of the peptide, we generated a control peptide TAT-BIND-S containing a scrambled amino acid sequence of BIND. We found that 10 μM TAT-BIND exerted no observable toxicity on control cells expressing (GGGGCC)2, but it completely suppressed cell death in (GGGGCC)66-expressing cells (Figure 1E). By contrast, the scrambled TAT-BIND-S had no effect on cells expressing (GGGGCC)2/66 (Figure 1E), indicating that the cell death-suppressing effect of TAT-BIND is dependent on its amino acid sequence. The calculated half-maximum inhibitory concentration (IC50) of TAT-BIND in inhibiting (GGGGCC)66-induced cell death is 103.9 ± 24.6 nM (Figure 1F). Ribonuclear foci, which contain aggregates of expanded GGGGCC RNA, are frequently found in the neurons of patients with C9ALS-FTD,44Conlon E.G. Lu L. Sharma A. Yamazaki T. Tang T. Shneider N.A. Manley J.L. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains.eLife. 2016; 5: e17820Crossref PubMed Scopus (172) Google Scholar, 45Jiang J. Zhu Q. Gendron T.F. Saberi S. McAlonis-Downes M. Seelman A. Stauffer J.E. Jafar-Nejad P. Drenner K. Schulte D. et al.Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.Neuron. 2016; 90: 535-550Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 46Gitler A.D. Tsuiji H. There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS.Brain Res. 2016; 1647: 19-29Crossref PubMed Scopus (103) Google Scholar and they are key indicators of RNA toxicity.42Gendron T.F. Bieniek K.F. Zhang Y.J. Jansen-West K. Ash P.E. Caulfield T. Daughrity L. Dunmore J.H. Castanedes-Casey M. Chew J. et al.Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS.Acta Neuropathol. 2013; 126: 829-844Crossref PubMed Scopus (385) Google Scholar, 47Mizielinska S. Lashley T. Norona F.E. Clayton E.L. Ridler C.E. Fratta P. Isaacs A.M. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci.Acta Neuropathol. 2013; 126: 845-857Crossref PubMed Scopus (221) Google Scholar, 48Lagier-Tourenne C. Baughn M. Rigo F. Sun S. Liu P. Li H.R. Jiang J. Watt A.T. Chun S. Katz M. et al.Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration.Proc. Natl. Acad. Sci. USA. 2013; 110: E4530-E4539Crossref PubMed Scopus (410) Google Scholar To determine whether TAT-BIND could inhibit the formation of GGGGCC RNA foci, we expressed (GGGGCC)2/66 in SK-N-MC cells, and we treated the cells with either TAT-BIND or TAT-BIND-S. We observed that TAT-BIND effectively suppressed foci formation in (GGGGCC)66-expressing cells, whereas TAT-BIND-S showed no modifying effect (Figures 2A and 2B ). These findings suggested that TAT-BIND mitigates the RNA toxicity caused by expanded GGGGCC. We further demonstrated that TAT-BIND did not alter the (GGGGCC)66 RNA level in (GGGGCC)66-expressing cells (Figure S1), which excluded the involvement of a toxic event led by a reduction in C9ORF72 expression. Ribonuclear foci are common signs, but not necessarily the main source of toxicity in patients with C9ALS-FTD. In fact, DPR proteins resulting from the RAN translation was also suggested as the major determinant of toxicity and degeneration in this disease.11Mizielinska S. Grönke S. Niccoli T. Ridler C.E. Clayton E.L. Devoy A. Moens T. Norona F.E. Woollacott I.O.C. Pietrzyk J. et al.C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.Science. 2014; 345: 1192-1194Crossref PubMed Scopus (452) Google Scholar, 49Tran H. Almeida S. Moore J. Gendron T.F. Chalasani U. Lu Y. Du X. Nickerson J.A. Petrucelli L. Weng Z. Gao F.B. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS.Neuron. 2015; 87: 1207-1214Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar In particular, three different types of DPR proteins, the poly-GR, poly-GA, and poly-GP, could be produced by RAN translation of GGGGCC repeats.15Lee Y.B. Baskaran P. Gomez-Deza J. Chen H.J. Nishimura A.L. Smith B.N. Troakes C. Adachi Y. Stepto A. Petrucelli L. et al.C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity.Hum. Mol. Genet. 2017; 26: 4765-4777Crossref PubMed Scopus (46) Google Scholar We sought to determine whether TAT-BIND has any effect on the formation of DPR proteins. Our western blot results showed that TAT-BIND, unlike its scrambled counterpart, significantly decreased the protein levels of poly-GR, poly-GA, and poly-GP DPR proteins (Figures 2C–2H), indicating that the peptide could also inhibit RAN translation of GGGGCC repeats. Since both GGGGCC RNA foci and DPR proteins have been shown to contribute to nucleolar stress in C9ALS-FTD, we speculated that TAT-BIND could relieve the nucleolar stress in cells expressing GGGGCC repeats. A reduction in rRNA maturation is considered as an indicator of nucleolar stress in C9ALS-FTD.16Haeusler A.R. Donnelly C.J. Periz G. Simko E.A. Shaw P.G. Kim M.S. Maragakis N.J. Troncoso J.C. Pandey A. Sattler R. et al.C9orf72 nucleotide repeat structures initiate molecular cascades of disease.Nature. 2014; 507: 195-200Crossref PubMed Scopus (624) Google Scholar We expressed (GGGGCC)66 in SK-N-MC cells, and we performed real-time PCR analysis on 45S pre-rRNA (pre-45 s rRNA), 28 s, 18 s, and 5.8 s rRNA. A general reduction in rRNA maturation was observed in these cells. Upon TAT-BIND treatment, (GGGGCC)66-expressing cells showed a significant restoration of pre-45 s, 18 s, and 5.8 s rRNA expression (Figure 3A). No such effect was observed in the TAT-BIND-S-treated cells. A similar trend was also observed for 28 s rRNA expression (Figure 3A). During nucleolar stress, the cell nucleolus rapidly loses its compact organization, and several nucleolar proteins, including NCL and nucleophosmin (B23), mislocalize to the nucleoplasm.16Haeusler A.R. Donnelly C.J. Periz G. Simko E.A. Shaw P.G. Kim M.S. Maragakis N.J. Troncoso J.C. Pandey A. Sattler R. et al.C9orf72 nucleotide repeat structures initiate molecular cascades of disease.Nature. 2014; 507: 195-200Crossref PubMed Scopus (624) Google Scholar, 17Tao Z. Wang H. Xia Q. Li K. Li K. Jiang X. Xu G. Wang G. Ying Z. Nucleolar stress and impaired stress granule formation contribute" @default.
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• W2917882620 title "A Peptidylic Inhibitor for Neutralizing (GGGGCC)-Associated Neurodegeneration in C9ALS-FTD" @default.
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