Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland.
BioEM Facility, EPFL - Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland.
Nat Commun. 2022 Aug 27;13(1):5049. doi: 10.1038/s41467-022-32683-5.
Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson's and late onset Alzheimer's disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.
微管相关蛋白 Tau 的水平、定位或翻译后加工的改变与许多神经退行性疾病有关。在这里，我们在果蝇中开发了人类 Tau（hTau）毒性的成年发病模型，除了对寿命的影响之外，这些模型还能够实现中枢神经系统突触丧失和轴突退化的年龄依赖性定量测量，从而有助于评估可能导致 Tau 依赖性神经退行性变的因素。使用这些模型，我们研究了 hTau 与逆行体复合物的相互作用，逆行体复合物是一种进化上保守的货物分拣蛋白组装体，其活性降低与帕金森病和迟发性阿尔茨海默病都有关。我们揭示了逆行体活性的降低通过 hTau 产生 C 末端截断同工型的特异性增加，诱导 hTau 毒性在突触丧失、轴突回缩和寿命方面的强烈增强。我们的数据建立了分子和亚细胞机制，对于逆行体活性的耗竭足以加剧 Tau 依赖性神经退行性变是必要和充分的。
