Small-molecule modulators of TRMT2A decrease PolyQ aggregation and PolyQ-induced cell death

Computational and Structural Biotechnology Journal, vol. 20, pp. 443–458

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.

Authors 18

1. Michael A. Margreiter Aachen Faculty of Mathematics, Computer Science and Natural Sciences

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, 52425 Aachen, Germany

   Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany

2. Monika Witzenberger

   Helmholtz Munich

   Affiliation as printed

   Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Structural Biology, 85764 Neuherberg, Germany

3. Yasmine Wasser Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

4. Elena Davydova

   Helmholtz Munich

   Affiliation as printed

   Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Structural Biology, 85764 Neuherberg, Germany

5. Robert Janowski

   Helmholtz Munich

   Affiliation as printed

   Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Structural Biology, 85764 Neuherberg, Germany

6. Jonas Metz

   Forschungszentrum Jülich

   Affiliation as printed

   Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany

7. Pardes Habib Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

   JARA - BRAIN - Translational Medicine, Aachen, Germany

8. Sabri E. M. Sahnoun Aachen Department of Nuclear Medicine

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany

9. Carina Sobisch Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

10. Benedetta Poma Aachen Department of Neurology

    RWTH Aachen University

    Affiliation as printed

    Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

11. Oscar Palomino‐Hernández Aachen Faculty of Mathematics, Computer Science and Natural Sciences

    RWTH Aachen University · Forschungszentrum Jülich

    Affiliation as printed

    Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen, 52425 Aachen, Germany

    Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany

12. Mirko Wagner

    Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany

13. Thomas Carell

    Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany

14. Nadim Jon Shah

    Forschungszentrum Jülich

    Affiliation as printed

    Institute of Neuroscience and Medicine (INM-11), Forschungszentrum Juelich GmbH, Germany

    Institute of Neuroscience and Medicine (INM-4), Forschungszentrum Juelich GmbH, Germany

    JARA - BRAIN - Translational Medicine, Aachen, Germany

15. Jörg Bernhard Schulz corresponding Aachen Department of Neurology

    RWTH Aachen University · Forschungszentrum Jülich

    Affiliation as printed

    Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

    Institute of Neuroscience and Medicine (INM-11), Forschungszentrum Juelich GmbH, Germany

    JARA - BRAIN - Translational Medicine, Aachen, Germany

16. Dierk Niessing corresponding

    Helmholtz Munich · Universität Ulm

    Affiliation as printed

    Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Structural Biology, 85764 Neuherberg, Germany

    Institute of Pharmaceutical Biotechnology, Ulm University, 89081 Ulm, Germany

17. Aaron Voigt corresponding Aachen Department of Neurology

    RWTH Aachen University

    Affiliation as printed

    Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

    JARA - BRAIN - Translational Medicine, Aachen, Germany

18. Giulia Rossetti corresponding Aachen Faculty of Medicine Department of Hematology, Oncology Department of Neurology

    RWTH Aachen University · Forschungszentrum Jülich · Jülich Supercomputing Centre

    Affiliation as printed

    Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

    Department of Neurology, RWTH University Aachen, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

    Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Juelich GmbH, Germany

    Juelich Supercomputing Center (JSC), Forschungszentrum Juelich GmbH, Germany