Partitioning-defective 1 (PAR-1), a conserved cell polarity regulator, plays an important role in synaptic development, and its mutation affects the formation of synaptic boutons and localization of postsynaptic density protein Discs large (Dlg) at the neuromuscular junction (NMJ) in Drosophila. Drosophila PAR-1 and its human homolog, Microtubule affinity-regulating kinases (MARK), are also known to be implicated in Alzheimer's disease (AD) by controlling tau-mediated Aβ toxicity. However, the molecular mechanisms of PAR-1 function remain incompletely understood. Here we identified Pod-1, an actin-microtubule crosslinker, which functionally and physically interacts with PAR-1 in Drosophila. Pod-1 prominently co-localizes with PAR-1 in the postsynaptic region and regulates PAR-1 activity at the NMJ. Synaptic defects, including the reduction of boutons and delocalization of Dlg caused by PAR-1 overexpression, were rescued by Pod-1 knockdown. Conversely, the reduction of synaptic boutons in PAR-1 overexpressed NMJ was synergistically enhanced by the overexpression of Pod-1. Furthermore, Pod-1 increases the PAR-1 dependent S262 phosphorylation of tau, which is known to contribute to tau-mediated Aβ toxicity. In line with the change of tau phosphorylation, Pod-1 knockdown rescued tau-mediated synaptic toxicity at the NMJ. Our results suggest that Pod-1 may act as a modulator of PAR-1 in synaptic development and tau-mediated toxicity.

中文翻译：

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肌动蛋白微管交联剂 Pod-1 调节 PAR-1 信号以控制突触发育和 tau 介导的突触毒性

Partitioning-defective 1 (PAR-1) 是一种保守的细胞极性调节因子，在突触发育中起着重要作用，其突变影响突触按钮的形成和突触后密度蛋白 Discs large (Dlg) 在神经肌肉接头 (NMJ) 的定位) 在果蝇中。果蝇 PAR-1 及其人类同源物微管亲和调节激酶 (MARK) 也通过控制 tau 介导的 Aβ 毒性与阿尔茨海默病 (AD) 相关。然而，PAR-1 功能的分子机制仍未完全了解。在这里，我们确定了 Pod-1，一种肌动蛋白-微管交联剂，它在功能上和物理上与果蝇中的 PAR-1 相互作用。Pod-1 在突触后区域与 PAR-1 显着共定位，并调节 NMJ 的 PAR-1 活性。突触缺陷，包括由 PAR-1 过表达引起的 boutons 的减少和 Dlg 的离域化，都被 Pod-1 击倒挽救了。相反，过表达 Pod-1 的 PAR-1 过表达 NMJ 中突触 boutons 的减少协同增强。此外，Pod-1 增加了 tau 的 PAR-1 依赖性 S262 磷酸化，已知这会导致 tau 介导的 Aβ 毒性。与 tau 磷酸化的变化一致，Pod-1 敲低在 NMJ 处挽救了 tau 介导的突触毒性。我们的研究结果表明，Pod-1 可能在突触发育和 tau 介导的毒性中充当 PAR-1 的调节剂。此外，Pod-1 增加了 tau 的 PAR-1 依赖性 S262 磷酸化，已知这会导致 tau 介导的 Aβ 毒性。与 tau 磷酸化的变化一致，Pod-1 敲低在 NMJ 处挽救了 tau 介导的突触毒性。我们的研究结果表明，Pod-1 可能在突触发育和 tau 介导的毒性中充当 PAR-1 的调节剂。此外，Pod-1 增加了 tau 的 PAR-1 依赖性 S262 磷酸化，已知这会导致 tau 介导的 Aβ 毒性。与 tau 磷酸化的变化一致，Pod-1 敲低在 NMJ 处挽救了 tau 介导的突触毒性。我们的研究结果表明，Pod-1 可能在突触发育和 tau 介导的毒性中充当 PAR-1 的调节剂。