Developmental expression of human tau in Drosophila melanogaster glial cells induces motor deficits and disrupts maintenance of PNS axonal integrity, without affecting synapse formation
Developmental expression of human tau in Drosophila melanogaster glial cells induces motor deficits and disrupts maintenance of PNS axonal integrity, without affecting synapse formation
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DOI：
10.1371/journal.pone.0226380
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发表时间：
2019-12
期刊：
影响因子：
3.7
通讯作者：
Enrico M Scarpelli;V. Y. Trinh;Zarrin Tashnim;J. Krans;Lani C Keller;Kenneth J. Colodner
中科院分区：
文献类型：
--
作者：
Enrico M Scarpelli;V. Y. Trinh;Zarrin Tashnim;J. Krans;Lani C Keller;Kenneth J. Colodner
tau蛋白病是一类神经退行性疾病，其特征在于微管相关蛋白tau在神经元和神经胶质细胞中的异常磷酸化和积累。虽然神经胶质细胞中的tau病理学是许多这些疾病的突出特征，但这些病变对tau病变发病机制的病理学贡献在很大程度上仍然未知。此外，虽然tau病理主要在中枢神经系统中发现，但已经描述了tau在外周神经系统细胞中的作用，尽管没有很好地表征。为了研究神经胶质tau蛋白表达对周围神经系统发育和维持的影响，我们利用了在发育过程中在神经胶质细胞中表达人野生型tau蛋白的黑腹果蝇tau蛋白病模型。我们发现，神经胶质tau蛋白的表达在发展过程中的幼虫的运动缺陷和生物体致死蛹阶段的结果，而不影响幼虫的神经肌肉接头突触发育或突触后振幅。然而，有一个显着减少突触电位的衰减时间后，重复刺激的运动神经元。行为异常伴随着神经胶质细胞死亡，破坏维护神经胶质轴突的完整性，和突触前蛋白，Bruchpilot，在外周神经轴突的异常积累。总之，这些数据表明果蝇胶质细胞中的人tau表达不会影响发育过程中神经肌肉接头突触的形成，但不利于维持周围神经系统中胶质-轴突相互作用。
Tauopathies are a class of neurodegenerative diseases characterized by the abnormal phosphorylation and accumulation of the microtubule-associated protein, tau, in both neuronal and glial cells. Though tau pathology in glial cells is a prominent feature of many of these disorders, the pathological contribution of these lesions to tauopathy pathogenesis remains largely unknown. Moreover, while tau pathology is predominantly found in the central nervous system, a role for tau in the cells of the peripheral nervous system has been described, though not well characterized. To investigate the effects of glial tau expression on the development and maintenance of the peripheral nervous system, we utilized a Drosophila melanogaster model of tauopathy that expresses human wild-type tau in glial cells during development. We found that glial tau expression during development results in larval locomotor deficits and organismal lethality at the pupal stage, without affecting larval neuromuscular junction synapse development or post-synaptic amplitude. There was, however, a significant decrease in the decay time of synaptic potentials upon repeated stimulation of the motoneuron. Behavioral abnormalities were accompanied by glial cell death, disrupted maintenance of glial-axonal integrity, and the abnormal accumulation of the presynaptic protein, Bruchpilot, in peripheral nerve axons. Together, these data demonstrate that human tau expression in Drosophila glial cells does not affect neuromuscular junction synapse formation during development, but is deleterious to the maintenance of glial-axonal interactions in the peripheral nervous system.