TY  - JOUR
AU  - Stahl, Fabian
AU  - Schmitt, Ina
AU  - Denner, Philip
AU  - de Boni, Laura
AU  - Wüllner, Ullrich
AU  - Breuer, Peter
TI  - High throughput compound screening in neuronal cells identifies statins as activators of ataxin 3 expression.
JO  - Scientific reports
VL  - 13
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2023-00893
SP  - 14911
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Ataxin-3: genetics
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
KW  - Neurons
KW  - Simvastatin
KW  - Spinocerebellar Ataxias
KW  - Ataxin-3 (NLM Chemicals)
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors (NLM Chemicals)
KW  - Simvastatin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10492798
C6  - pmid:37689718
DO  - DOI:10.1038/s41598-023-41192-4
UR  - https://pub.dzne.de/record/263808
ER  -