PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43
PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43
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DOI：
10.1093/hmg/ddu587
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发表时间：
2015-03-15
影响因子：
3.5
通讯作者：
Zarnescu, Daniela C.
中科院分区：
文献类型：
--
作者：
Joardar, Archi;Menzl, Judith;Zarnescu, Daniela C.
肌萎缩侧索硬化症（ALS）是一种进行性神经肌肉疾病，目前尚无治愈方法。我们以前已经开发了一种基于TDP-43的ALS果蝇模型，该模型概括了疾病病理生理学的几个方面。使用这个模型，我们设计了一个药物筛选策略的基础上的蛹致死表型诱导TDP-43时，在运动神经元中表达。在筛选1200种FDA批准的化合物时，我们确定了PPAR γ激动剂吡格列酮在果蝇中具有神经保护作用。在这里，我们表明，吡格列酮可以挽救TDP-43依赖运动神经元和神经胶质，但不是在肌肉运动功能障碍。测试ALS的其他模型，我们发现当FUS而不是SOD 1在运动神经元中表达时，吡格列酮也具有神经保护作用。有趣的是，TDP或FUS模型的生存分析显示寿命没有增加，这与最近的临床试验一致。使用药物遗传学的方法，我们表明，预测的果蝇PPAR γ同系物，E75和E78，是吡格列酮在体内的目标。最后，使用全局代谢组学方法，我们确定了一组代谢产物，吡格列酮可以恢复的TDP-43在运动神经元中的表达。综上所述，我们的数据提供了证据表明，调节PPAR γ活性，虽然不能有效地提高寿命，但提供了一个减轻TDP-43和FUS运动功能障碍的分子靶点，而不是果蝇ALS的SOD 1模型。此外，我们的数据还确定了该疾病的几种“生物标志物”，这些生物标志物可能有助于开发治疗方法和未来的临床试验。
Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. We have previously developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of disease pathophysiology. Using this model, we designed a drug screening strategy based on the pupal lethality phenotype induced by TDP-43 when expressed in motor neurons. In screening 1200 FDA-approved compounds, we identified the PPAR gamma agonist pioglitazone as neuroprotective in Drosophila. Here, we show that pioglitazone can rescue TDP-43-dependent locomotor dysfunction in motor neurons and glia but not in muscles. Testing additional models of ALS, we find that pioglitazone is also neuroprotective when FUS, but not SOD1, is expressed in motor neurons. Interestingly, survival analyses of TDP or FUS models show no increase in lifespan, which is consistent with recent clinical trials. Using a pharmacogenetic approach, we show that the predicted Drosophila PPAR gamma homologs, E75 and E78, are in vivo targets of pioglitazone. Finally, using a global metabolomic approach, we identify a set of metabolites that pioglitazone can restore in the context of TDP-43 expression in motor neurons. Taken together, our data provide evidence that modulating PPAR gamma activity, although not effective at improving lifespan, provides a molecular target for mitigating locomotor dysfunction in TDP-43 and FUS but not SOD1 models of ALS in Drosophila. Furthermore, our data also identify several 'biomarkers' of the disease that may be useful in developing therapeutics and in future clinical trials.