G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson's Disease Patients
G1/S Cell Cycle Checkpoint Dysfunction in Lymphoblasts from Sporadic Parkinson's Disease Patients
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DOI：
10.1007/s12035-014-8870-y
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发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Martin-Requero, Angeles
中科院分区：
文献类型：
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作者：
Esteras, Noemi;Alquezar, Carolina;Martin-Requero, Angeles
帕金森病（Parkinson's disease，PD）是老年人中第二大常见的神经退行性疾病，严重影响老年人的生活质量。然而，帕金森病的发病机制至今仍不完全清楚。越来越多的实验证据表明，有丝分裂后神经元的细胞周期重新进入之前，许多情况下的神经元死亡。由于细胞周期功能障碍并不局限于神经元，我们研究了这个问题，在外周细胞从患者患有散发性PD和年龄匹配的控制个人。在这里，我们描述了PD患者永生化淋巴细胞的细胞周期活性增加，这与细胞周期蛋白D3/CDK 6复合物的活性增强有关，导致pRb家族蛋白的磷酸化水平升高，从而导致G（1）/S调控失败。在PD淋巴母细胞中发现细胞周期蛋白D3降解减少，p21降解增加，以及CDK 6 mRNA和蛋白水平升高。细胞周期蛋白D3/CDK 6活性抑制剂如丁酸钠、PD-332991和雷帕霉素能够恢复PD细胞对血清刺激的反应。我们的结论是，淋巴母细胞从PD患者是一个合适的模型，调查这种疾病的细胞生化方面。这表明，细胞周期蛋白D3/CDK 6相关激酶活性可能是一个潜在的治疗PD的新的治疗靶点。
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among aging individuals, affecting greatly the quality of their life. However, the pathogenesis of Parkinson's disease is still incompletely understood to date. Increasing experimental evidence suggests that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Since cell cycle dysfunction is not restricted to neurons, we investigated this issue in peripheral cells from patients suffering from sporadic PD and age-matched control individuals. Here, we describe increased cell cycle activity in immortalized lymphocytes from PD patients that is associated to enhanced activity of the cyclin D3/CDK6 complex, resulting in higher phosphorylation of the pRb family protein and thus, in a G(1)/S regulatory failure. Decreased degradation of cyclin D3, together with increased p21 degradation, as well as elevated levels of CDK6 mRNA and protein were found in PD lymphoblasts. Inhibitors of cyclin D3/CDK6 activity like sodium butyrate, PD-332991, and rapamycin were able to restore the response of PD cells to serum stimulation. We conclude that lymphoblasts from PD patients are a suitable model to investigate cell biochemical aspects of this disease. It is suggested that cyclin D3/CDK6-associated kinase activity could be potentially a novel therapeutic target for the treatment of PD.