Ayyadevara Srinivas, Balasubramaniam Meenakshisundaram, Kakraba Samuel, Alla Ramani, Mehta Jawahar L, Shmookler Reis Robert J
1 Central Arkansas Veterans Healthcare System, Research & Development Service , Little Rock, Arkansas.
2 Department of Geriatrics, Reynolds Institute on Aging, University of Arkansas for Medical Sciences , Little Rock, Arkansas.
Antioxid Redox Signal. 2017 Dec 10;27(17):1383-1396. doi: 10.1089/ars.2016.6978. Epub 2017 Jun 28.
Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets.
Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides.
Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions.
These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio-protective, and life-prolonging effects of aspirin. Antioxid. Redox Signal. 27, 1383-1396.
许多进行性神经疾病，包括阿尔茨海默病（AD）、亨廷顿舞蹈病和帕金森病（PD），其特征是不溶性蛋白质聚集体的积累。在前瞻性试验中，环氧化酶抑制剂阿司匹林（乙酰水杨酸）降低了患AD和PD的风险，以及心血管事件和许多迟发性癌症的风险。考虑到蛋白质过度磷酸化在聚集和神经退行性疾病中所起的作用，以及阿司匹林已知的提供乙酰基的能力，我们探究阿司匹林是否可能通过乙酰化蛋白质靶点来减少磷酸化和聚集。
在体外培养的人神经母细胞瘤细胞以及体内人类神经退行性疾病的秀丽隐杆线虫模型中，阿司匹林在减少或延迟聚集方面比水杨酸盐有效得多。阿司匹林使许多蛋白质乙酰化，同时减少磷酸化，这表明乙酰化可能与磷酸化相反。令人惊讶的是，乙酰化蛋白质在很大程度上被排除在紧密聚集体之外。分子动力学模拟表明，淀粉样肽的乙酰化在能量上不利于其形成二聚体和八聚体，并且形成的寡聚体比那些由未乙酰化肽组成的寡聚体更不紧密、更不稳定。
过度磷酸化使某些蛋白质易于聚集（例如tau蛋白、α-突触核蛋白和反式激活反应DNA结合蛋白43 [TDP-43]），并且它是心血管疾病和神经退行性疾病中的关键致病标志物。我们提供了新的证据，表明乙酰化蛋白质在蛋白质聚集体中的含量较低，并且在各种基因和药物干预后，聚集与乙酰化倾向呈负相关。
这些结果与以下假设一致，即阿司匹林通过其提供乙酰基的活性抑制蛋白质聚集以及聚集物随后产生的毒性。这种机制可能有助于阿司匹林的神经保护、心脏保护和延长寿命的作用。《抗氧化与氧化还原信号》27, 1383 - 1396。
