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001     263808
005     20240112171337.0
024 7 _ |a pmc:PMC10492798
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024 7 _ |a 10.1038/s41598-023-41192-4
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024 7 _ |a pmid:37689718
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037 _ _ |a DZNE-2023-00893
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Stahl, Fabian
|0 P:(DE-2719)2812610
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245 _ _ |a High throughput compound screening in neuronal cells identifies statins as activators of ataxin 3 expression.
260 _ _ |a [London]
|c 2023
|b Macmillan Publishers Limited, part of Springer Nature
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520 _ _ |a The 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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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Ataxin-3: genetics
|2 MeSH
650 _ 2 |a Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Neurons
|2 MeSH
650 _ 2 |a Simvastatin
|2 MeSH
650 _ 2 |a Spinocerebellar Ataxias
|2 MeSH
650 _ 7 |a Ataxin-3
|0 EC 3.4.19.12
|2 NLM Chemicals
650 _ 7 |a Hydroxymethylglutaryl-CoA Reductase Inhibitors
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650 _ 7 |a Simvastatin
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|e Laboratory Automation Technologies (CRFS-LAT) / Bonn
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700 1 _ |a Schmitt, Ina
|b 1
700 1 _ |a Denner, Philip
|0 P:(DE-2719)2810245
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700 1 _ |a de Boni, Laura
|b 3
700 1 _ |a Wüllner, Ullrich
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700 1 _ |a Breuer, Peter
|0 P:(DE-2719)9002874
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773 _ _ |a 10.1038/s41598-023-41192-4
|g Vol. 13, no. 1, p. 14911
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|t Scientific reports
|v 13
|y 2023
|x 2045-2322
856 4 _ |y OpenAccess
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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