Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Hum Mol Genet. 2012 Jan 15;21(2):237-50. doi: 10.1093/hmg/ddr449. Epub 2011 Sep 30.
Tauopathies, including Alzheimer's disease, are a group of neurodegenerative diseases characterized by abnormal tau hyperphosphorylation that leads to formation of neurofibrillary tangles. Drosophila models of tauopathy display prominent features of the human disease including compromised lifespan, impairments of learning, memory and locomotor functions and age-dependent neurodegeneration visible as vacuolization. Here, we use a Drosophila model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), in order to study the neuroprotective capacity of a recently identified neuronal maintenance factor, nicotinamide mononucleotide (NAD) adenylyl transferase (NMNAT), a protein that has both NAD synthase and chaperone function. NMNAT is essential for maintaining neuronal integrity under normal conditions and has been shown to protect against several neurodegenerative conditions. However, its protective role in tauopathy has not been examined. Here, we show that overexpression of NMNAT significantly suppresses both behavioral and morphological deficits associated with tauopathy by means of reducing the levels of hyperphosphorylated tau oligomers. Importantly, the protective activity of NMNAT protein is independent of its NAD synthesis activity, indicating a role for direct protein-protein interaction. Next, we show that NMNAT interacts with phosphorylated tau in vivo and promotes the ubiquitination and clearance of toxic tau species. Consequently, apoptosis activation was significantly reduced in brains overexpressing NMNAT, and neurodegeneration was suppressed. Our report on the molecular basis of NMNAT-mediated neuroprotection in tauopathies opens future investigation of this factor in other protein foldopathies.
tau 病，包括阿尔茨海默病，是一组神经退行性疾病，其特征是异常 tau 过度磷酸化，导致神经原纤维缠结的形成。tau 病的果蝇模型显示出人类疾病的显著特征，包括寿命缩短、学习、记忆和运动功能受损以及与年龄相关的神经退行性变，表现为空泡化。在这里，我们使用一种与 17 号染色体相关的额颞叶痴呆伴帕金森病的果蝇模型（FTDP-17），以研究最近发现的神经元维持因子烟酰胺单核苷酸（NAD）腺苷酰转移酶（NMNAT）的神经保护能力，这种蛋白具有 NAD 合酶和伴侣功能。NMNAT 在正常情况下对维持神经元完整性是必不可少的，并且已经被证明可以预防几种神经退行性疾病。然而，它在 tau 病中的保护作用尚未被研究。在这里，我们发现 NMNAT 的过表达通过降低过度磷酸化 tau 寡聚物的水平，显著抑制与 tau 病相关的行为和形态缺陷。重要的是，NMNAT 蛋白的保护活性与其 NAD 合成活性无关，表明存在直接的蛋白-蛋白相互作用。接下来，我们发现 NMNAT 在体内与磷酸化 tau 相互作用，并促进有毒 tau 物种的泛素化和清除。因此，在过表达 NMNAT 的大脑中，细胞凋亡的激活显著减少，神经退行性变得到抑制。我们关于 NMNAT 在 tau 病中介导神经保护的分子基础的报告为研究该因子在其他蛋白质折叠病中的作用开辟了未来的研究方向。
