Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.
Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.
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DOI：
10.1186/s40478-016-0333-4
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发表时间：
2016-06-23
影响因子：
7.1
通讯作者：
Shulman JM
中科院分区：
文献类型：
--
作者：
Chouhan AK;Guo C;Hsieh YC;Ye H;Senturk M;Zuo Z;Li Y;Chatterjee S;Botas J;Jackson GR;Bellen HJ;Shulman JM
常见的神经退行性蛋白质病，如阿尔茨海默病（AD）和帕金森病（PD），其特征在于毒性蛋白质种类的错误折叠和聚集，包括淀粉样蛋白β（A β）肽、微管相关蛋白Tau（Tau）和α-突触核蛋白（αSyn）蛋白。这些因素在果蝇中也显示出毒性;然而，先前研究的潜在局限性包括对成人与发育中的神经系统以及神经元与神经胶质细胞类型的影响之间的区分不佳。此外，可变的表达模式和结果阻碍了毒性特征的系统比较。使用标准化条件和中等通量测定，我们在成年果蝇视网膜的神经元中选择性地表达人Tau、Akt或αSyn，并分别基于组织组织学和视网膜电图（ERG）记录来监测结构和功能的年龄依赖性变化。我们发现，每种蛋白质导致神经退行性病理学的独特的配置文件，表现出不同的和可分离的影响神经元死亡和功能障碍。引人注目的是，Tau的表达导致ERG反应的进行性丧失，而视网膜结构和神经元数量在很大程度上得以保留。相比之下，Ablast诱导适度的年龄依赖性神经元损失，而不降低视网膜ERG。使用密码子优化的转基因表达αSyn的特征是明显的视网膜空泡变化、进行性感光细胞死亡以及延迟发生但适度的ERG变化。最后，为了解决潜在的机制，我们进行透射电子显微镜（TEM），以揭示潜在的退行性变化在超微结构水平。令人惊讶的是，Tau和αSyn分别引起显著但不同的突触毒性特征，包括感光体末端的解体或扩大。我们的研究结果突出了由这些疾病相关蛋白在体内引发的神经变性的可变和动态特性，并表明果蝇可能有助于揭示成年神经系统中细胞丢失之前的神经元功能障碍的决定因素，包括突触变化。本文的在线版本（doi：10.1186/s40478-016-0333-4）包含补充材料，可供授权用户使用。
Common neurodegenerative proteinopathies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system. The online version of this article (doi:10.1186/s40478-016-0333-4) contains supplementary material, which is available to authorized users.