Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington's Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens

Autor: Albert Giralt, Jordi Alberch, Mercè Masana, Verónica Brito, Anna Castañé, Esther Sieiro, Aida Royes, Silvia Ginés, Marc Espina, Jean-Antoine Girault
Přispěvatelé: Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Generalitat de Catalunya, Institut National de la Santé et de la Recherche Médicale (France), Université Pierre et Marie Curie, Fondation pour la Recherche Médicale, Laboratory of Excellence of Biology for Psychiatry (France)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
Dopamine and cAMP-Regulated Phosphoprotein 32
Dendritic spine
Huntingtin
CDK5
Population
Nucleus accumbens
Huntington's chorea
Nucleus Accumbens
Dendritic spines
03 medical and health sciences
Mice
Mice
Neurologic Mutants
0302 clinical medicine
Huntington's disease
β-adducin
Corea de Huntington
Dopamine
Internal medicine
Neural Pathways
medicine
Animals
Phosphorylation
Depressió psíquica
education
Depressive-like behavior
Biological Psychiatry
education.field_of_study
business.industry
Cyclin-dependent kinase 5
Cyclin-Dependent Kinase 5
medicine.disease
DARPP-32
Cytoskeletal Proteins
030104 developmental biology
Endocrinology
Huntington Disease
Mental depression
nervous system
Antidepressant
Female
business
030217 neurology & neurosurgery
medicine.drug
Huntington’s disease
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Dipòsit Digital de la UB
Universidad de Barcelona
Popis: [Background] Depression is the most common psychiatric condition in Huntington’s disease (HD), with rates more than twice those found in the general population. At the present time, there is no established molecular evidence to use as a basis for depression treatment in HD. Indeed, in some patients, classic antidepressant drugs exacerbate chorea or anxiety. Cyclin-dependent kinase 5 (Cdk5) has been involved in processes associated with anxiety and depression. This study evaluated the involvement of Cdk5 in the development and prevalence of depressive-like behaviors in HD and aimed to validate Cdk5 as a target for depression treatment. [Methods] We evaluated the impact of pharmacological inhibition of Cdk5 in depressive-like and anxiety-like behaviors in Hdh+/Q111 knock-in mutant mice by using a battery of behavioral tests. Biochemical and morphological studies were performed to define the molecular mechanisms acting downstream of Cdk5 activation. A double huntingtin/DARPP-32 (dopamine- and cAMP-regulated phosphoprotein 32) knock-in mutant mouse was generated to analyze the role of DARPP-32 in HD depression. [Results] We found that Hdh+/Q111 mutant mice exhibited depressive-like, but not anxiety-like, behaviors starting at 2 months of age. Cdk5 inhibition by roscovitine infusion prevented depressive-like behavior and reduced DARPP-32 phosphorylation at Thr75 in the nucleus accumbens. Hdh+/Q111 mice heterozygous for DARPP-32 Thr75Ala point mutation were resistant to depressive-like behaviors. We identified β-adducin phosphorylation as a Cdk5 downstream mechanism potentially mediating structural spine plasticity changes in the nucleus accumbens and depressive-like behavior. [Conclusions] These results point to Cdk5 in the nucleus accumbens as a critical contributor to depressive-like behaviors in HD mice by altering DARPP-32/β-adducin signaling and disrupting the dendritic spine cytoskeleton.
This work was supported by the Ministerio de Economía y Competitividad (Grant No. SAF2015-67474-R;MINECO/FEDER [to SG] and Grant No. SAF2017-88076-R [to JA]), Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (Grant No. CB06/05/0054 [to JA]), Agencia de Gestión de Ayudas Universitarias y de Investigación (Grant No. 2017SGR717 [to AC]). and Ramon y Cajal fellowship (Grant No. RYC-2016-19466 [to AG]). J-AG’s laboratory was supported in part by Inserm, the Université Pierre et Marie Curie (Sorbonne Université), the Fondation pour la Recherche Médicale, and the Laboratory of Excellence of Biology for Psychiatry.
Databáze: OpenAIRE
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