Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease
- University of Barcelona, Spain
- William Harvey Research Institute, Queen Mary University of London, United Kingdom
- University of Trento, Italy
- Instituto Ramon y Cajal de Investigacion Sanitaria, Universidad Complutense, Spain
- Queen Mary University of London, United Kingdom
- University of Pisa, Italy
- 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
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.
Reviewing Editor
- Volker Dötsch, Goethe University, Germany
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.
Version history
- Received: August 14, 2019
- Accepted: May 26, 2020
- Accepted Manuscript published: June 9, 2020 (version 1)
- Version of Record published: June 9, 2020 (version 2)
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.
Metrics
-
- 3,103
- views
-
- 299
- downloads
-
- 21
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Cell Biology
- Neuroscience
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
-
- Genetics and Genomics
- Neuroscience
Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.
