Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness.
Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness.
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DOI：
10.1186/1472-6793-11-7
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发表时间：
2011-04-25
期刊：
影响因子：
--
通讯作者：
Schwartz LM
中科院分区：
文献类型：
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作者：
Kim C;Srivastava S;Rice M;Godenschwege TA;Bentley B;Ravi S;Shao S;Woodard CT;Schwartz LM
阿尔茨海默病和几种其他退行性疾病如包涵体肌炎的标志之一是淀粉样前体蛋白（APP）及其蛋白水解淀粉样肽的异常积累。为了更好地了解APP不适当表达对发育组织的病理后果，我们产生了转基因苍蝇，表达野生型人类APP的骨骼肌，然后进行解剖，电生理和行为分析的成年人。我们观察到，在这些转基因动物中，肌肉发育和动物寿命都没有受到影响。然而，表达APP的成年人在攀爬和飞行方面都出现了年龄依赖性缺陷。我们可以通过在具有不同表面特性的小瓶中饲养动物来提前或延迟症状的发作，这表明人类APP表达介导的行为缺陷受到肌肉活动的影响。转基因动物的肌肉在光镜或透射电镜水平上没有显示蛋白质聚集或结构异常。与对发育中的哺乳动物成肌细胞进行的遗传研究一致，我们观察到泛素E3连接酶Parkin的共表达可以改善人类APP诱导的缺陷。这些数据表明：1）人类APP在果蝇中的异位表达导致年龄和活动依赖性行为缺陷，而肌肉发育或结构没有明显变化; 2）环境影响可以极大地改变人类APP毒性的表型结果; 3）APP诱导的病理学的遗传修饰剂可以在该模型中鉴定和分析。
One of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults. We observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects. These data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.