RT Journal Article
T1 Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington’sdisease
A1 Moreno-Delgado, David
A1 Puigdellívol, Mar
A1 Moreno, Moreno
A1 Rodríguez-Ruiz, Mar
A1 Botta, Joaquín
A1 Gasperini, Paola
A1 Chiarlone, Anna
A1 Howell, Lesley A.
A1 Scarselli, Marco
A1 Casadó, Vicent
A1 Cortés, Antoni
A1 Ferré, Sergi
A1 Guzmán, Manuel
A1 Lluís, Carmen
A1 Alberch, Jordi
A1 Canela, Enric I.
A1 Ginés, Silvia
A1 McCormick, Peter J.
AB 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.
PB eLife Sciences Publications
SN ESSN 2050-084X
YR 2020
FD 2020-06-09
LK https://hdl.handle.net/20.500.14352/6622
UL https://hdl.handle.net/20.500.14352/6622
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Ministerio de Ciencia, Innovación y Universidades (MCIU)
NO Centro de Investigación Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED)
NO Red de Terapia Celular (RETICS)
NO Fundació La Marató de TV3
NO Royal Society of Chemistry (London)
NO Jerome LeJeune Foundation (Paris)
NO Queen Mary University of London
DS Docta Complutense
RD 6 abr 2025