Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila.
Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila.
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DOI：
10.1007/s13238-011-1073-7
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发表时间：
2011-07
期刊：
影响因子：
21.1
通讯作者：
Bier E
中科院分区：
文献类型：
--
作者：
Wangler MF;Reiter LT;Zimm G;Trimble-Morgan J;Wu J;Bier E
阿尔茨海默病（AD）的发病机制以脑内老年斑和氧化损伤为特征。氧化应激可能先于斑块形成；然而，氧化损伤和斑块形成之间的联系尚不清楚。早老素是一种跨膜蛋白，其突变可导致加速斑块形成和早发性家族性阿尔茨海默病。早老素与过氧化氧还蛋白家族的两种抗氧化酶硫醇特异性抗氧化酶（TSA）和增殖相关基因（PAG）相互作用。这些相互作用的功能后果尚不清楚。在本研究中，我们在果蝇的翅膀和果蝇的感觉器官前体中表达了早老素转基因。这导致了典型的Notch信号功能丧失突变的表型。我们发现，虽然单独表达TSA或PAG不会产生表型，但TSA和PAG与早老素的共同表达会导致Notch功能丧失表型的增强。这种表型比单独表达Psn引起的表型更严重，渗透性更强。为了确定这些表型是否确实影响Notch信号，本实验在携带激活的Notch （Abruptex）等位基因的遗传背景下进行。这个激活的Notch等位基因几乎完全挽救了表型。这些结果将过氧化物还毒素与早老素的体内功能联系起来，最终将AD的两个关键发病机制，即抗氧化活性和斑块形成联系起来，并提出了过氧化物还毒素家族成员在阿尔茨海默病发病中的作用的可能性。
Alzheimer's disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer's disease. Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. The functional consequences of these interactions are unclear. In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. This caused phenotypes typical of Notch signaling loss-of-function mutations. We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. This phenotype was more severe and more penetrant than that caused by the expression of Psn alone. In order to determine whether these phenotypes were indeed affecting Notch signaling, this experiment was performed in a genetic background carrying an activated Notch (Abruptex) allele. The phenotypes were almost completely rescued by this activated Notch allele. These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer's pathogenesis.
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