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Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death
Michael A Margreiter1,2, Monika Witzenberger3, Yasmine Wasser4
1Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany.
Abstract:
Polyglutamine (polyQ) diseases are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in Drosophila melanogaster. This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases in humans. Computer-aided drug discovery was implemented to identify human TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined, and Biacore experiments with the RRM were performed. The identified molecules were validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Our work provides a first step towards pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.
Insights
Researchers identified TRMT2A inhibitors to treat polyglutamine (polyQ) diseases. These compounds reduced polyQ aggregation and cell death, indicating TRMT2A is a viable drug target for these neurodegenerative conditions.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Polyglutamine (polyQ) diseases stem from expanded CAG trinucleotide repeats.
- TRMT2A was previously identified as a key modifier of polyQ toxicity in Drosophila.
- Targeting TRMT2A offers a potential therapeutic strategy for polyQ diseases.
Purpose of the Study:
- To identify and validate pharmacological TRMT2A inhibitors for human polyQ diseases.
- To explore TRMT2A as a druggable target for polyQ disease treatment.
Main Methods:
- Computer-aided drug discovery for TRMT2A inhibitors.
- Crystal structure determination of the TRMT2A RNA recognition motif (RRM).
- Biacore experiments to characterize RRM interactions.
- In vitro validation in HEK293T cells and patient-derived fibroblasts.
Main Results:
- Identification of novel human TRMT2A inhibitors.
- Structural insights into the TRMT2A RRM domain.
- Demonstrated reduction of polyQ aggregation by identified compounds.
- Validated efficacy in reducing polyQ-induced cell death in human cell models.
Conclusions:
- TRMT2A is a viable drug target for polyQ diseases.
- Pharmacological inhibition of TRMT2A is a promising therapeutic avenue.
- This study represents a significant first step towards developing TRMT2A-based therapies.
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