Functional and Morphological Correlates in the Drosophila LRRK2 loss-of-function Model of Parkinson's Disease: Drug Effects of Withania somnifera (Dunal) Administration.
Functional and Morphological Correlates in the Drosophila LRRK2 loss-of-function Model of Parkinson's Disease: Drug Effects of Withania somnifera (Dunal) Administration.
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DOI：
10.1371/journal.pone.0146140
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Liscia A
中科院分区：
文献类型：
--
作者：
De Rose F;Marotta R;Poddighe S;Talani G;Catelani T;Setzu MD;Solla P;Marrosu F;Sanna E;Kasture S;Acquas E;Liscia A
果蝇（Drosophila melanogaster，Dm）是一种简单的动物，对神经生物学的发展有重要贡献，其富含亮氨酸的重复序列激酶2（LRRK 2）在WD 40结构域的功能丧失是研究帕金森病（PD）病理生理学的一个非常有趣的工具。因此，LRRK 2 Dm也有可能有助于揭示其治疗的创新治疗方法。Withania somnifera Dunal是一种在地中海地区自发生长的植物，在民间医学中以其抗炎和保护神经变性的特性而闻名。本研究的目的是评估其标准化的根甲醇提取物（WSE）对PD的LRRK 2功能丧失DM模型的神经保护作用。为此，突变体和野生型（WT）果蝇通过饮食以不同浓度作为幼虫和成虫（L+/A+）或仅作为成虫（L-/A+）给予Wse。与WT果蝇1%Wse-富集饮食相比，LRRK 2突变体具有显著降低的寿命和受损的运动功能和线粒体形态，以L-/A+给予Dm LRRK 2，并改善a）运动活性B）对刺激的肌肉电生理反应，以及c）保护免于线粒体变性。相比之下，Wse以L+/A+形式给予Dm LRRK 2，无论在哪个浓度下，都会使寿命恶化，并确定胸神经节中内体活性增加的外观。这些结果在证实WD 40结构域中的LRRK 2功能丧失代表PD的有效模型的同时，揭示了在适当浓度下，Wse可以有效地用于抵消与疾病相关的一些缺陷。然而，需要仔细评估可能与内体活性受损相关的风险。
The common fruit fly Drosophila melanogaster (Dm) is a simple animal species that contributed significantly to the development of neurobiology whose leucine-rich repeat kinase 2 mutants (LRRK2) loss-of-function in the WD40 domain represent a very interesting tool to look into physiopathology of Parkinson’s disease (PD). Accordingly, LRRK2 Dm have also the potential to contribute to reveal innovative therapeutic approaches to its treatment. Withania somnifera Dunal, a plant that grows spontaneously also in Mediterranean regions, is known in folk medicine for its anti-inflammatory and protective properties against neurodegeneration. The aim of this study was to evaluate the neuroprotective effects of its standardized root methanolic extract (Wse) on the LRRK2 loss-of-function Dm model of PD. To this end mutant and wild type (WT) flies were administered Wse, through diet, at different concentrations as larvae and adults (L+/A+) or as adults (L-/A+) only. LRRK2 mutants have a significantly reduced lifespan and compromised motor function and mitochondrial morphology compared to WT flies 1% Wse-enriched diet, administered to Dm LRRK2 as L-/A+and improved a) locomotor activity b) muscle electrophysiological response to stimuli and also c) protected against mitochondria degeneration. In contrast, the administration of Wse to Dm LRRK2 as L+/A+, no matter at which concentration, worsened lifespan and determined the appearance of increased endosomal activity in the thoracic ganglia. These results, while confirming that the LRRK2 loss-of-function in the WD40 domain represents a valid model of PD, reveal that under appropriate concentrations Wse can be usefully employed to counteract some deficits associated with the disease. However, a careful assessment of the risks, likely related to the impaired endosomal activity, is required.