Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease

  1. David Moreno-Delgado
  2. Mar Puigdellivol
  3. Estefanía Moreno
  4. Mar Rodríguez-Ruiz
  5. Joaquín Botta
  6. Paola Gasperini
  7. Anna Chiarlone
  8. Lesley A Howell
  9. Marco Scarselli
  10. Vicent Casadó
  11. Antoni Cortés
  12. Sergi Ferré
  13. Manuel Guzmán
  14. Carmen Lluís
  15. Jordi Alberch
  16. Enric I Canela
  17. Silvia Ginés  Is a corresponding author
  18. Peter J McCormick  Is a corresponding author
  1. University of Barcelona, Spain
  2. William Harvey Research Institute, Queen Mary University of London, United Kingdom
  3. University of Trento, Italy
  4. Instituto Ramon y Cajal de Investigacion Sanitaria, Universidad Complutense, Spain
  5. Queen Mary University of London, United Kingdom
  6. University of Pisa, Italy
  7. National Institutes of Health, United States

Abstract

Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. David Moreno-Delgado

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Mar Puigdellivol

    Biomedical Science, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Estefanía Moreno

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Mar Rodríguez-Ruiz

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Joaquín Botta

    Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6450-1267
  6. Paola Gasperini

    CIBIO, University of Trento, Trento, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Anna Chiarlone

    Deparment of Biochemistry and Molecular Biology, Instituto Ramon y Cajal de Investigacion Sanitaria, Universidad Complutense, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Lesley A Howell

    Chemistry, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Marco Scarselli

    Pharmacology, University of Pisa, Pisa, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Vicent Casadó

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Antoni Cortés

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. Sergi Ferré

    NIDA, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Manuel Guzmán

    Deparment of Biochemistry and Molecular Biology, Instituto Ramon y Cajal de Investigacion Sanitaria, Universidad Complutense, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  14. Carmen Lluís

    Biochemistry, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  15. Jordi Alberch

    Biomedical Sciences, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8684-2721
  16. Enric I Canela

    Biochemistry and Molecular Bomedicine, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4992-7440
  17. Silvia Ginés

    Biomedical Science, University of Barcelona, Barcelona, Spain
    For correspondence
    silviagines@ub.edu
    Competing interests
    The authors declare that no competing interests exist.
  18. Peter J McCormick

    Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
    For correspondence
    p.mccormick@qmul.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2225-5181

Funding

BBSRC CASE (MCCORMICK_U15BB)

  • Peter J McCormick

RSC Grant Project (RG140118)

  • Peter J McCormick

BBSRC (BB/N504282/3)

  • Peter J McCormick

Ministerio de Economia y Competitividad (RTI2018-094374-B-I00)

  • Silvia Ginés

Fundació la Marató de TV3 (20140610)

  • Enric I Canela

Jerome LeJeune Foundation (FJL-01/01/2013)

  • Peter J McCormick

Ministerio de Economia y Competitividad (SAF2017-88076-R)

  • Jordi Alberch

Ministerio de Economia y Competitividad (RTI2018-095311-B-I00)

  • Manuel Guzmán

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures involving animals were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the local animal care committee of the Universitat de Barcelona (99/01) and Generalitat de Catalunya (99/1094), in accordance with the European (2010/63/EU) and Spanish (RD53/2013) regulations for the care and use of laboratory animals. All protocols involving postmortem human sample were approved by the institutional ethic committees.

Copyright

© 2020, Moreno-Delgado et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. David Moreno-Delgado
  2. Mar Puigdellivol
  3. Estefanía Moreno
  4. Mar Rodríguez-Ruiz
  5. Joaquín Botta
  6. Paola Gasperini
  7. Anna Chiarlone
  8. Lesley A Howell
  9. Marco Scarselli
  10. Vicent Casadó
  11. Antoni Cortés
  12. Sergi Ferré
  13. Manuel Guzmán
  14. Carmen Lluís
  15. Jordi Alberch
  16. Enric I Canela
  17. Silvia Ginés
  18. Peter J McCormick
(2020)
Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease
eLife 9:e51093.
https://doi.org/10.7554/eLife.51093

Share this article

https://doi.org/10.7554/eLife.51093

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