Frank H. Netter, M.D. School of Medicine, Quinnipiac University, North Haven, CT, United States of America.
Department of Biological Sciences, Quinnipiac University, Hamden, CT, United States of America.
PLoS One. 2019 Dec 10;14(12):e0226380. doi: 10.1371/journal.pone.0226380. eCollection 2019.
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.
tau 病是一类以微管相关蛋白 tau 的异常磷酸化和积累为特征的神经退行性疾病，存在于神经元和神经胶质细胞中。尽管 tau 病理学在神经胶质细胞中是许多此类疾病的一个显著特征，但这些病变对 tau 病发病机制的病理贡献在很大程度上仍然未知。此外，虽然 tau 病理学主要存在于中枢神经系统中，但已经描述了 tau 在周围神经系统细胞中的作用，尽管尚未得到很好的描述。为了研究神经胶质细胞 tau 表达对周围神经系统发育和维持的影响，我们利用了一个表达人类野生型 tau 的黑腹果蝇 tau 病模型，在发育过程中在神经胶质细胞中表达。我们发现，在发育过程中表达神经胶质 tau 会导致幼虫运动功能缺陷和蛹期的个体死亡，而不影响幼虫神经肌肉接头突触的发育或突触后振幅。然而，在重复刺激运动神经元时，突触电位的衰减时间显著减少。行为异常伴随着神经胶质细胞死亡、神经胶质-轴突完整性的破坏以及周围神经轴突中突触前蛋白 Bruchpilot 的异常积累。总之，这些数据表明，在果蝇神经胶质细胞中表达人类 tau 不会影响发育过程中神经肌肉接头突触的形成，但对周围神经系统中神经胶质-轴突相互作用的维持是有害的。
