Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity
Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity
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DOI：
10.1093/hmg/ddv107
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发表时间：
2015-07-01
影响因子：
3.5
通讯作者：
Voigt, Aaron
中科院分区：
文献类型：
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作者：
Butzlaff, Malte;Hannan, Shabab B.;Voigt, Aaron
该基因图谱编码微管相关蛋白Tau。Tau中的R406 W氨基酸取代与17号染色体（FTDP-17）相关的额颞叶痴呆伴帕金森综合征相关，其特征在于Tau阳性丝状包涵体。这些丝状Tau内含物存在于一组称为Tau蛋白病的神经退行性疾病中，包括阿尔茨海默病（AD）。为了更深入地了解tau蛋白病的病理机制，我们在黑腹果蝇中进行了基于RNAi的大规模筛选，以鉴定Tau[R406 W]诱导毒性的遗传修饰剂。筛选了一组RNAi系（puronums沉默超过7000个基因）在体内修饰Tau[R406 W]诱导的毒性的能力。该集合涵盖了超过50%的所有蛋白质编码苍蝇基因和超过90%的已知具有人类直系同源物的所有苍蝇基因。因此，我们鉴定了62个基因，当被RNAi沉默时，特异性地修饰了Tau诱导的毒性。在这62种修饰剂中，动力蛋白/动力肌动蛋白复合物的三个亚基。对蝇幼虫的节段神经的分析显示，泛神经Tau[R406 W]表达和动力蛋白/动力蛋白复合物成员的伴随沉默协同地引起轴突隔室内的强烈病理变化，但在突触处仅引起微小变化。在幼虫阶段，这些变化并没有造成运动缺陷，但在成年苍蝇变得明显。我们的数据表明，Tau诱导的有害作用最有可能起源于轴突而不是突触功能障碍，并且受损的逆行转运加剧了Tau在轴突中的有害作用。总之，我们的研究结果有助于阐明tau蛋白病如FTDP-17或AD的疾病机制。
The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present in a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To gain more insights into the pathomechanism of tauopathies, we performed an RNAi-based large-scale screen in Drosophila melanogaster to identify genetic modifiers of Tau[R406W]-induced toxicity. A collection of RNAi lines, putatively silencing more than 7000 genes, was screened for the ability to modify Tau[R406W]-induced toxicity in vivo. This collection covered more than 50% of all protein coding fly genes and more than 90% of all fly genes known to have a human ortholog. Hereby, we identified 62 genes that, when silenced by RNAi, modified Tau-induced toxicity specifically. Among these 62 modifiers were three subunits of the Dynein/Dynactin complex. Analysis on segmental nerves of fly larvae showed that pan neural Tau[R406W] expression and concomitant silencing of Dynein/Dynactin complex members synergistically caused strong pathological changes within the axonal compartment, but only minor changes at synapses. At the larval stage, these alterations did not cause locomotion deficits, but became evident in adult flies. Our data suggest that Tau-induced detrimental effects most likely originate from axonal rather than synaptic dysfunction and that impaired retrograde transport intensifies detrimental effects of Tau in axons. In conclusion, our findings contribute to the elucidation of disease mechanisms in tauopathies like FTDP-17 or AD.