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000263808 1001_ $$0P:(DE-2719)2812610$$aStahl, Fabian$$b0$$eFirst author
000263808 245__ $$aHigh throughput compound screening in neuronal cells identifies statins as activators of ataxin 3 expression.
000263808 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2023
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000263808 520__ $$aThe spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. SCA3 is the most common form, caused by the expansion of CAG repeats within the ataxin 3 (ATXN3) gene. The mutation results in the expression of an abnormal protein, containing long polyglutamine (polyQ) stretches. The polyQ stretch confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. Thus, modulators of ATXN3 expression could potentially ameliorate the pathology in SCA3 patients. Therefore, we generated a CRISPR/Cas9 modified ATXN3-Exon4-Luciferase (ATXN3-LUC) genomic fusion- and control cell lines to perform a reporter cell line-based high-throughput screen comprising 2640 bioactive compounds, including the FDA approved drugs. We found no unequivocal inhibitors of, but identified statins as activators of the LUC signal in the ATXN3-LUC screening cell line. We further confirmed that Simvastatin treatment of wild type SK-N-SH cells increases ATXN3 mRNA and protein levels which likely results from direct binding of the activated sterol regulatory element binding protein 1 (SREBP1) to the ATXN3 promotor. Finally, we observed an increase of normal and expanded ATXN3 protein levels in a patient-derived cell line upon Simvastatin treatment, underscoring the potential medical relevance of our findings.
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000263808 650_2 $$2MeSH$$aHumans
000263808 650_2 $$2MeSH$$aAtaxin-3: genetics
000263808 650_2 $$2MeSH$$aHydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
000263808 650_2 $$2MeSH$$aNeurons
000263808 650_2 $$2MeSH$$aSimvastatin
000263808 650_2 $$2MeSH$$aSpinocerebellar Ataxias
000263808 650_7 $$0EC 3.4.19.12$$2NLM Chemicals$$aAtaxin-3
000263808 650_7 $$2NLM Chemicals$$aHydroxymethylglutaryl-CoA Reductase Inhibitors
000263808 650_7 $$0AGG2FN16EV$$2NLM Chemicals$$aSimvastatin
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000263808 7001_ $$aSchmitt, Ina$$b1
000263808 7001_ $$0P:(DE-2719)2810245$$aDenner, Philip$$b2
000263808 7001_ $$ade Boni, Laura$$b3
000263808 7001_ $$0P:(DE-2719)2000056$$aWüllner, Ullrich$$b4
000263808 7001_ $$0P:(DE-2719)9002874$$aBreuer, Peter$$b5$$eLast author$$udzne
000263808 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-023-41192-4$$gVol. 13, no. 1, p. 14911$$n1$$p14911$$tScientific reports$$v13$$x2045-2322$$y2023
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