Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630W 168th St., New York, NY, 10032, USA.
Neuromolecular Med. 2013 Dec;15(4):720-36. doi: 10.1007/s12017-013-8257-7. Epub 2013 Aug 25.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly. Histopathologically, AD features insoluble aggregates of two proteins in the brain, amyloid-β (Aβ) and the microtubule-associated protein tau, both of which have been linked to the small ubiquitin-like modifier (SUMO). A large body of research has elucidated many of the molecular and cellular pathways that underlie AD, including those involving the abnormal Aβ and tau aggregates. However, a full understanding of the etiology and pathogenesis of the disease has remained elusive. Consequently, there are currently no effective therapeutic options that can modify the disease progression and slow or stop the decline of cognitive functioning. As part of the effort to address this lacking, there needs a better understanding of the signaling pathways that become impaired under AD pathology, including the regulatory mechanisms that normally control those networks. One such mechanism involves SUMOylation, which is a post-translational modification (PTM) that is involved in regulating many aspects of cell biology and has also been found to have several critical neuron-specific roles. Early studies have indicated that the SUMO system is likely altered with AD-type pathology, which may impact Aβ levels and tau aggregation. Although still a relatively unexplored topic, SUMOylation will likely emerge as a significant factor in AD pathogenesis in ways which may be somewhat analogous to other regulatory PTMs such as phosphorylation. Thus, in addition to the upstream effects on tau and Aβ processing, there may also be downstream effects mediated by Aβ aggregates or other AD-related factors on SUMO-regulated signaling pathways. Multiple proteins that have functions relevant to AD pathology have been identified as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics, and inflammatory signaling. Ongoing studies will determine how these SUMO-regulated functions in neurons and glial cells may be impacted by Aβ and AD pathology. Here, we present a review of the current literature on the involvement of SUMO in AD, as well as an overview of the SUMOylated proteins and pathways that are potentially dysregulated with AD pathogenesis.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性认知能力下降，是老年人中最常见的痴呆症病因。组织病理学上，AD 以大脑中两种蛋白质（淀粉样β（Aβ）和微管相关蛋白 tau）的不溶性聚集体为特征，这两种蛋白质都与小泛素样修饰物（SUMO）有关。大量研究阐明了许多导致 AD 的分子和细胞途径，包括涉及异常 Aβ和 tau 聚集体的途径。然而，对该疾病的病因和发病机制仍未完全了解。因此，目前尚无有效的治疗方法可以改变疾病进展，减缓或阻止认知功能下降。作为解决这一问题的努力的一部分，需要更好地了解 AD 病理下受损的信号通路，包括正常控制这些网络的调节机制。其中一种机制涉及 SUMO 化，这是一种参与调节细胞生物学许多方面的翻译后修饰（PTM），并且已经发现它在神经元中具有几个关键作用。早期研究表明，SUMO 系统可能会随着 AD 样病理学而改变，这可能会影响 Aβ 水平和 tau 聚集。尽管 SUMO 化仍然是一个相对未知的课题，但 SUMO 化可能会作为 AD 发病机制中的一个重要因素出现，其方式可能与其他调节 PTM （如磷酸化）有些类似。因此，除了对 tau 和 Aβ 加工的上游影响外，Aβ 聚集或其他与 AD 相关的因素可能还会对 SUMO 调节的信号通路产生下游影响。已经确定了许多与 AD 病理学相关的具有功能的蛋白质作为 SUMO 底物，包括参与突触生理学、线粒体动力学和炎症信号的蛋白质。正在进行的研究将确定神经元和神经胶质细胞中的这些 SUMO 调节功能如何受到 Aβ 和 AD 病理学的影响。在这里，我们回顾了目前关于 SUMO 在 AD 中的作用的文献，并概述了与 AD 发病机制相关的潜在失调的 SUMO 化蛋白和途径。
