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Title: Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease
Author: Moreno Delgado, David
Puigdellívol Cañadell, Maria del Mar
Moreno Guillén, Estefanía
Rodríguez Ruiz, Mar
Botta, Joaquín
Gasperini, Paola
Chiarlone, Anna
Howell, Lesley A.
Scarselli, Marco
Casadó, Vicent
Cortés Tejedor, Antonio
Ferré, Sergi
Guzmán, Manuel
Lluís i Biset, Carme
Alberch i Vié, Jordi
Canela Campos, Enric I.
Ginés Padrós, Silvia
McCormick, Peter J.
Keywords: Corea de Huntington
Huntington's chorea
Issue Date: 9-Jun-2020
Publisher: eLife Sciences
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.
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It is part of: eLife, 2020, vol. 9, p. e51093
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ISSN: 2050-084X
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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