Pre-fibrillar α-synuclein mutants cause Parkinson's disease-like non-motor symptoms in Drosophila.
Pre-fibrillar α-synuclein mutants cause Parkinson's disease-like non-motor symptoms in Drosophila.
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DOI：
10.1371/journal.pone.0024701
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jäckle H
中科院分区：
文献类型：
--
作者：
Gajula Balija MB;Griesinger C;Herzig A;Zweckstetter M;Jäckle H
帕金森病（PD）与突触前蛋白α-突触核蛋白（αS）在神经元中形成不溶性纤维状聚集体有关。这种聚集体的出现与人类患者的严重运动缺陷相吻合。这些缺陷通常伴随着非运动症状，如患者的睡眠相关问题。当αS被泛神经表达时，PD样运动缺陷可以在模式生物如黑腹果蝇中重现。有趣的是，当聚集特性降低的αS突变体在果蝇中表达时，这两种缺陷都更严重。这表明αS聚集不是PD样运动症状的主要原因。在这里，我们描述了一个模型，PD在果蝇中，利用靶向表达αS突变体的一个子集的多巴胺脱羧酶表达多巴胺能和多巴胺能（DA）神经元。我们的研究结果表明，前纤维αS突变体的靶向表达不仅重现了PD样运动症状，而且还重现了之前的非运动症状，如异常的睡眠样行为，改变的运动活动和异常的昼夜节律周期。此外，结果表明，在苍蝇中观察到的非运动症状是由神经元功能的早期损伤引起的，而不是由于细胞死亡引起的神经元损失。
Parkinson's disease (PD) is linked to the formation of insoluble fibrillar aggregates of the presynaptic protein α-Synuclein (αS) in neurons. The appearance of such aggregates coincides with severe motor deficits in human patients. These deficits are often preceded by non-motor symptoms such as sleep-related problems in the patients. PD-like motor deficits can be recapitulated in model organisms such as Drosophila melanogaster when αS is pan-neurally expressed. Interestingly, both these deficits are more severe when αS mutants with reduced aggregation properties are expressed in flies. This indicates that that αS aggregation is not the primary cause of the PD-like motor symptoms. Here we describe a model for PD in Drosophila which utilizes the targeted expression of αS mutants in a subset of dopadecarboxylase expressing serotonergic and dopaminergic (DA) neurons. Our results show that targeted expression of pre-fibrillar αS mutants not only recapitulates PD-like motor symptoms but also the preceding non-motor symptoms such as an abnormal sleep-like behavior, altered locomotor activity and abnormal circadian periodicity. Further, the results suggest that the observed non-motor symptoms in flies are caused by an early impairment of neuronal functions rather than by the loss of neurons due to cell death.
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DOI：
10.1073/pnas.0901148106
发表时间：
2009-07-21
影响因子：
11.1
作者：
Chanana, Bhavna;Steigemann, Patrick;Vorbrueggen, Gerd
通讯作者：
Vorbrueggen, Gerd
影响因子：
5.3
作者：
Kume, K;Kume, S;Jackson, FR
通讯作者：
Jackson, FR
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
11.4
作者：
Karpinar, Damla Pinar;Balija, Madhu Babu Gajula;Zweckstetter, Markus
通讯作者：
Zweckstetter, Markus
影响因子：
4.8
作者：
Arnulf, Isabelle;Leu, Smaranda;Oudiette, Delphine
通讯作者：
Oudiette, Delphine