Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
J Biol Chem. 2011 Oct 14;286(41):35689-35698. doi: 10.1074/jbc.M111.243147. Epub 2011 Aug 18.
Alzheimer disease (AD) is associated with extracellular deposition of proteolytic fragments of amyloid precursor protein (APP). Although mutations in APP and proteases that mediate its processing are known to result in familial, early onset forms of AD, the mechanisms underlying the more common sporadic, yet genetically complex forms of the disease are still unclear. Four single-nucleotide polymorphisms within the ubiquilin-1 gene have been shown to be genetically associated with AD, implicating its gene product in the pathogenesis of late onset AD. However, genetic linkage between ubiquilin-1 and AD has not been confirmed in studies examining different populations. Here we show that regardless of genotype, ubiquilin-1 protein levels are significantly decreased in late onset AD patient brains, suggesting that diminished ubiquilin function may be a common denominator in AD progression. Our interrogation of putative ubiquilin-1 activities based on sequence similarities to proteins involved in cellular quality control showed that ubiquilin-1 can be biochemically defined as a bona fide molecular chaperone and that this activity is capable of preventing the aggregation of amyloid precursor protein both in vitro and in live neurons. Furthermore, we show that reduced activity of ubiquilin-1 results in augmented production of pathogenic amyloid precursor protein fragments as well as increased neuronal death. Our results support the notion that ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis.
阿尔茨海默病（AD）与淀粉样前体蛋白（APP）的蛋白水解片段的细胞外沉积有关。虽然 APP 中的突变和介导其加工的蛋白酶已知会导致家族性、早发性 AD，但导致更常见的散发性、遗传复杂形式的疾病的机制仍不清楚。在泛素蛋白-1 基因内的四个单核苷酸多态性已被证明与 AD 具有遗传相关性，这表明其基因产物与晚发性 AD 的发病机制有关。然而，在研究不同人群的研究中，泛素蛋白-1 与 AD 之间的遗传连锁尚未得到证实。在这里，我们表明，无论基因型如何，泛素蛋白-1 蛋白水平在晚发性 AD 患者的大脑中显著降低，这表明泛素蛋白功能的降低可能是 AD 进展的一个共同因素。我们根据与参与细胞质量控制的蛋白质的序列相似性对假定的泛素蛋白-1 活性进行了探究，结果表明，泛素蛋白-1 可以被生化定义为真正的分子伴侣，并且这种活性能够防止淀粉样前体蛋白在体外和活神经元中的聚集。此外，我们还表明，泛素蛋白-1 活性的降低会导致致病性淀粉样前体蛋白片段的产生增加，以及神经元死亡增加。我们的研究结果支持这样一种观点，即泛素蛋白-1 伴侣活性对于调节 APP 的产生及其片段是必要的，并且泛素蛋白-1 水平的降低可能会导致 AD 的发病机制。
