Yates Sharon C, Zafar Amen, Rabai Erzsebet M, Foxall James B, Nagy Sheila, Morrison Karen E, Clarke Carl, Esiri Margaret M, Christie Sharon, Smith A David, Nagy Zsuzsanna
Neuropharmacology and Neurobiology, College of Medical and Dental Sciences, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
Department of Neuropathology, University of Oxford, Level 1, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
PLoS One. 2015 Jan 27;10(1):e0114050. doi: 10.1371/journal.pone.0114050. eCollection 2015.
With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.
除了载脂蛋白E4（ApoE4）外，全基因组关联研究未能识别出散发性阿尔茨海默病的强遗传风险因素，尽管有强有力的遗传证据表明可能涉及许多低外显率基因。此外，已识别出的遗传风险因素的性质及其与疾病病理学的关系在很大程度上也不清楚。先前的研究发现，细胞周期抑制剂基因p21cip1的一种癌症相关变体与阿尔茨海默病风险增加有关。本研究的目的是证实这种关联，并阐明该变体对蛋白质功能和阿尔茨海默病型病理学的影响。我们研究了p21cip1变体与阿尔茨海默病和帕金森病伴痴呆的关联。基因分型研究在牛津记忆与衰老调查项目的719名参与者、帕金森病DNA库的225名参与者以及欧洲细胞培养物保藏中心提供的人类随机对照样本的477名参与者中进行。尸检研究在190名参与者中开展。在体外研究中，用常见或罕见的p21cip1变体转染人胚肾细胞；并使用细胞计数法评估细胞周期动力学、p21cip1蛋白表达和亚细胞定位。相对于年龄匹配的对照组，该变体与阿尔茨海默病以及帕金森病伴痴呆的风险增加相关。此外，该变体与阿尔茨海默病的发病年龄较早以及更严重的表型相关，主要影响缠结病理学的积累。在体外研究中，我们发现这些单核苷酸多态性降低了p21cip1的细胞周期抑制和抗凋亡活性。结果表明，p21cip1的癌症相关变体可能导致神经元细胞周期控制丧失，进而可能导致阿尔茨海默病型神经退行性变。
