The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer's disease.
The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer's disease.
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DOI：
10.1186/s13195-020-00732-0
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发表时间：
2020-12-03
期刊：
影响因子：
--
通讯作者：
Uberti D
中科院分区：
文献类型：
--
作者：
Abate G;Frisoni GB;Bourdon JC;Piccirella S;Memo M;Uberti D
了解阿尔茨海默病（AD）最早期的病理生理学变化可能有助于寻找及时的诊断生物标志物和有效的疾病修饰疗法。p53蛋白主要以其在肿瘤抑制中的作用而闻名。然而，新出现的证据支持，失调的p53活性可能有助于在AD的最早阶段的各种外周和大脑的变化。这篇综述描述了p53失调可能加剧AD病理的机制，以及如何将其用作早期检测该疾病的潜在外周生物标志物。p53被称为基因组的守护者，可能是防止神经元退化的各种补偿或防御机制的基础。这些机制包括维持氧化还原稳态、调节炎症、控制突触功能、减少淀粉样β肽和抑制神经元细胞周期再进入。因此，p53依赖性补偿机制的失调可能导致神经元功能障碍，从而导致神经变性。有趣的是，在轻度认知障碍（MCI）和AD患者的外周细胞中观察到p53的构象错误折叠变体，在文献中描述为未折叠的p53，其已经失去了其典型的结构和功能。在AD病理学中，这种特殊的构象变体是由翻译后修饰引起的，而不是癌症中常见的突变。虽然p53的构象变体在大脑中的存在尚未得到正式证明，但过多的p53依赖性补偿机制强调了基因组的监护人可能不仅在AD病理过程中在外周中丢失。这些发现重新审视了p53在AD病理学的早期发展和恶化中的作用，无论是在大脑还是外周。p53的构象变体代表了一种潜在的外周生物标志物，可以在其最早阶段检测AD。
Understanding the earliest pathophysiological changes of Alzheimer’s disease (AD) may aid in the search for timely diagnostic biomarkers and effective disease-modifying therapies. The p53 protein is mostly known for its role in tumor suppression. However, emerging evidence supports that dysregulated p53 activity may contribute to various peripheral and brain alterations during the earliest stages of AD. This review describes the mechanisms through which p53 dysregulation may exacerbate AD pathology and how this could be used as a potential peripheral biomarker for early detection of the disease. p53, known as the guardian of the genome, may underlie various compensation or defense mechanisms that prevent neurons from degeneration. These mechanisms include maintenance of redox homeostasis, regulation of inflammation, control of synaptic function, reduction of amyloid β peptides, and inhibition of neuronal cell cycle re-entry. Thereby, dysregulation of p53-dependent compensation mechanisms may contribute to neuronal dysfunction, thus leading to neurodegeneration. Interestingly, a conformational misfolded variant of p53, described in the literature as unfolded p53, which has lost its canonical structure and function, was observed in peripheral cells from mild cognitive impairment (MCI) and AD patients. In AD pathology, this peculiar conformational variant was caused by post-translational modifications rather than mutations as commonly observed in cancer. Although the presence of the conformational variant of p53 in the brain has yet to be formally demonstrated, the plethora of p53-dependent compensation mechanisms underscores that the guardian of the genome may not only be lost in the periphery during AD pathology. These findings revisit the role of p53 in the early development and exacerbation of AD pathology, both in the brain and periphery. The conformational variant of p53 represents a potential peripheral biomarker that could detect AD at its earliest stages.
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发表时间：
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期刊：
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影响因子：
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作者：
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