周期蛋白依赖性激酶 5 功能障碍通过改变伏隔核中的 DARPP-32 磷酸化状态导致亨廷顿病的抑郁样行为。

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.

机构信息

Department of Biomedical Science, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.

出版信息

Biol Psychiatry. 2019 Aug 1;86(3):196-207. doi: 10.1016/j.biopsych.2019.03.001. Epub 2019 Mar 13.

DOI:10.1016/j.biopsych.2019.03.001

PMID:31060804

Abstract

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 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 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 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.

摘要

背景

抑郁症是亨廷顿病（HD）中最常见的精神疾病，其发病率是普通人群的两倍以上。目前，尚无确立的分子证据可作为 HD 抑郁症治疗的基础。事实上，在某些患者中，经典抗抑郁药会加重舞蹈症或焦虑。细胞周期蛋白依赖性激酶 5（Cdk5）参与了与焦虑和抑郁相关的过程。本研究评估了 Cdk5 在 HD 发展和抑郁样行为中的作用，并旨在验证 Cdk5 作为抗抑郁治疗的靶点。

方法

我们通过一系列行为测试评估了 Cdk5 药理学抑制对 Hdh 敲入突变小鼠抑郁样和焦虑样行为的影响。进行了生化和形态学研究，以确定 Cdk5 激活下游的分子机制。生成了双重亨廷顿蛋白/DARPP-32（多巴胺和 cAMP 调节的磷酸蛋白 32）敲入突变小鼠，以分析 DARPP-32 在 HD 抑郁症中的作用。

结果

我们发现，Hdh 突变小鼠从 2 个月大开始表现出抑郁样行为，但没有焦虑样行为。罗克洛维丁输注抑制 Cdk5 可防止抑郁样行为，并减少伏隔核中 DARPP-32 的 Thr75 磷酸化。DARPP-32 Thr75Ala 点突变杂合的 Hdh 小鼠对抑郁样行为具有抗性。我们确定β-辅肌动蛋白磷酸化是一种 Cdk5 下游机制，可能介导伏隔核中结构棘突可塑性变化和抑郁样行为。