Pin1 protein associates with neuronal lipofuscin: Potential consequences in age-related neurodegeneration
Pin1 protein associates with neuronal lipofuscin: Potential consequences in age-related neurodegeneration
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DOI：
10.1016/j.expneurol.2005.12.030
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Thorpe, Julian Robert
中科院分区：
文献类型：
--
作者：
Hashemzadeh-Bonehi, Lida;Phillips, Roger Guy;Thorpe, Julian Robert
Pin 1蛋白是一种肽基脯氨酰顺反异构酶，可调节一系列参与细胞功能的蛋白质的活性。我们和其他人已经证明了阿尔茨海默病（AD）中的神经元Pin 1缺陷，并在额颞叶痴呆和衰老中表现出类似的缺陷。事实上，Pin 1可能是一个易感因子;其他人已经表明Pin 1缺失会导致HeLa细胞凋亡。此外，AD病理模式与正常人脑中Pin 1表达较低的区域相关; Pin 1敲除小鼠患有神经变性; Pin 1可以通过异构化p-tau，促进其反式特异性去磷酸化并恢复其结合和重新稳定微管的能力以及细胞骨架完整性来改善p-tau病理。在这里，我们报告了一种新的定位高水平的Pin 1与脂褐素在老化的神经元。这种关联可能会逐渐耗尽可用的Pin 1，并在衰老过程中对神经元功能有害。我们还表明，当脂褐素积累变得明显时，Pin 1与脂褐素相关，并与神经退行性疾病的易感性相关。我们的数据与神经元Pin 1缺陷可能是与衰老相关的神经退行性变的一个促成因素的可能性是一致的。(c)2006年爱思唯尔公司All rights reserved.
Pin1 protein is a peptidyl-prolyl cis-trans isomerase that modulates the activity of a range of proteins involved in cell function. We and others have demonstrated neuronal Pin1 deficits in Alzheimer's disease (AD) and have shown similar deficits in frontotemporal dementia and in aging. Pin1 may, in fact, be a susceptibility factor; others have shown that Pin1 depletion causes apoptosis in HeLa cells. Further, patterns of AD pathology correlate with regions of lower Pin1 expression in normal human brain; Pin1 knockout mice suffer neurodegeneration; and Pin1 can ameliorate p-tau pathology by isomerizing p-tau, facilitating its trans-specific dephosphorylation and restoring its ability to bind to and restabilize microtubules and thence cytoskeletal integrity. Here, we report a novel localization of high levels of Pin1 with lipofuscin in aging neurons. This association could progressively drain available Pin1 and be deleterious to neuronal function during aging. We also show that Pin1 associates with lipofuscin when lipofuscin accumulations become marked and correlate with susceptibility to neurodegenerative disease. Our data are consistent with the possibility that neuronal Pin1 deficits may be a contributory factor in neurodegeneration associated with aging. (c) 2006 Elsevier Inc. All rights reserved.