Journal Article

DZNE-2023-00893

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png High throughput compound screening in neuronal cells identifies statins as activators of ataxin 3 expression.

Stahl, F. (First author)DZNE* ; Schmitt, I. ; Denner, P.DZNE* ; de Boni, L. ; Wüllner, U.DZNE* ; Breuer, P. (Last author)DZNE*

2023
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-023-41192-4

Abstract: 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.

Keyword(s): Humans (MeSH) ; Ataxin-3: genetics (MeSH) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology (MeSH) ; Neurons (MeSH) ; Simvastatin (MeSH) ; Spinocerebellar Ataxias (MeSH) ; Ataxin-3 ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Simvastatin

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Contributing Institute(s):

1. Biomarker Parkinson's Disease (AG Wüllner)
2. Laboratory Automation Technologies (LAT) (LAT)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Experiment(s):

1. Laboratory Automation Technologies (CRFS-LAT) / Bonn

Appears in the scientific report 2023

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