High throughput compound screening in neuronal cells identifies statins as activators of ataxin 3 expression

Author:

Stahl Fabian,Schmitt Ina,Denner Philip,de Boni Laura,Wüllner Ullrich,Breuer Peter

Abstract

AbstractThe 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.

Funder

Novartis Stiftung für therapeutische Forschung

Deutsches Zentrum für Neurodegenerative Erkrankungen

Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE) in der Helmholtz-Gemeinschaft

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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