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000164645 0247_ $$2doi$$a10.1016/j.celrep.2022.110913
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000164645 0247_ $$2ISSN$$a2639-1856
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000164645 037__ $$aDZNE-2022-01175
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000164645 1001_ $$0P:(DE-2719)2811917$$aCzuppa, Mareike$$b0$$eFirst author$$udzne
000164645 245__ $$aDrug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD
000164645 260__ $$a[New York, NY]$$bElsevier$$c2022
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000164645 520__ $$aAn intronic (G4C2)n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders.
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000164645 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000164645 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000164645 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000164645 650_2 $$2MeSH$$aAnimals
000164645 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000164645 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000164645 650_2 $$2MeSH$$aDNA Repeat Expansion
000164645 650_2 $$2MeSH$$aDecitabine: metabolism
000164645 650_2 $$2MeSH$$aDipeptides: metabolism
000164645 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000164645 650_2 $$2MeSH$$aHumans
000164645 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000164645 650_2 $$2MeSH$$aMice
000164645 650_2 $$2MeSH$$aNeurons: metabolism
000164645 650_2 $$2MeSH$$aNucleosides: metabolism
000164645 650_2 $$2MeSH$$aRNA, Antisense: metabolism
000164645 7001_ $$0P:(DE-2719)2811729$$aDhingra, Ashutosh$$b1$$udzne
000164645 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b2$$udzne
000164645 7001_ $$0P:(DE-2719)9001337$$aSchludi, Carina$$b3$$udzne
000164645 7001_ $$0P:(DE-2719)9001381$$aKoenig, Laura$$b4$$udzne
000164645 7001_ $$0P:(DE-2719)9001326$$aScharf, Elisabeth$$b5$$udzne
000164645 7001_ $$0P:(DE-2719)2812127$$aFarny, Daniel$$b6$$udzne
000164645 7001_ $$0P:(DE-2719)2812478$$aDalmia, Anupriya$$b7$$udzne
000164645 7001_ $$0P:(DE-2719)2811804$$aTäger, Joachim$$b8$$udzne
000164645 7001_ $$0P:(DE-2719)2810917$$aCastillo Lizardo, Melissa Gissel$$b9$$udzne
000164645 7001_ $$0P:(DE-2719)9001378$$aKatona, Eszter$$b10$$udzne
000164645 7001_ $$aMori, Kohji$$b11
000164645 7001_ $$aAumer, Tina$$b12
000164645 7001_ $$aSchelter, Florian$$b13
000164645 7001_ $$aMüller, Markus$$b14
000164645 7001_ $$aCarell, Thomas$$b15
000164645 7001_ $$00000-0001-8037-2434$$aKalliokoski, Tuomo$$b16
000164645 7001_ $$aMessinger, Josef$$b17
000164645 7001_ $$0P:(DE-2719)2810718$$aRizzu, Patrizia$$b18$$udzne
000164645 7001_ $$0P:(DE-2719)2810728$$aHeutink, Peter$$b19$$udzne
000164645 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b20$$eLast author$$udzne
000164645 773__ $$0PERI:(DE-600)2649101-1$$a10.1016/j.celrep.2022.110913$$gVol. 39, no. 10, p. 110913 -$$n10$$p110913$$tCell reports$$v39$$x2211-1247$$y2022
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