A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration
A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration
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DOI：
10.1016/j.neuron.2006.07.019
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发表时间：
2006-09-07
期刊：
影响因子：
16.2
通讯作者：
Jackson, George R.
中科院分区：
文献类型：
--
作者：
Karsten, Stanislav L.;Sang, Tzu-Kang;Jackson, George R.
含有tau的神经原纤维缠结(NFT)是包括阿尔茨海默病(AD)在内的神经退行性疾病的标志。NFT负荷与AD患者认知功能减退和神经退行性变相关。然而，人们对tau诱导的神经变性的保护机制知之甚少。我们使用跨物种功能基因组方法分析了小鼠多个脑区的基因表达，同时在果蝇中进行了验证，以确定tau修饰物，包括高度保守的蛋白质嘌呤霉素敏感氨基肽酶(PSA/NPepps)。在体内，PSA对tau诱导的神经退变具有保护作用，而PSA功能丧失则加剧了神经退变。我们进一步证明，人的PSA在体外可以直接分解tau蛋白。这些数据突显了使用进化上遥远的物种进行遗传筛选和功能评估以确定神经退行性变的修饰因素的效用。有必要进行进一步的研究，以确定PSA和其他基因在直肠反复症中的潜在治疗靶点的作用。
Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration. We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps). PSA protected against tau-induced neurodegeneration in vivo, whereas PSA loss of function exacerbated neurodegeneration. We further show that human PSA directly proteolyzes tau in vitro. These data highlight the utility of using both evolutionarily distant species for genetic screening and functional assessment to identify modifiers of neurodegeneration. Further investigation is warranted in defining the role of PSA and other genes identified here as potential therapeutic targets in tauopathy.