Neurodegenerative tauopathies such as Alzheimer's and Parkinson's diseases are characterized by hyperphosphorylation of tau protein and their subsequent aggregation in the forms of paired helical filaments and/or neurofibrillary tangles in specific areas of the brain. Despite several attempts, it remains a challenge to develop reliable biomarkers or effective drugs against tauopathies. It is increasingly evident now that due to the involvement of multiple cellular cascades affected by the pathogenic tau molecules, a single genetic modifier or a molecule is unlikely to be efficient enough to provide an inclusive rescue. Hence, multitargets based combinatorial approach(s) have been suggested to provide an efficient rescue against tauopathies. We have reported earlier that targeted downregulation of dmyc (a Drosophila homolog of human cmyc proto-oncogene) restricts tau etiology by limiting tau hyperphosphorylation and heterochromatin loss. Although, dmyc generates a significant rescue; however, it is not proficient enough to provide a complete alleviation against tauopathies. Here, we report that tissue-specific concurrent downregulation of dmyc and gsk3β conveys a near-complete rescue against tau toxicity in Drosophila. We noted that combinatorial downregulation of dmyc and gsk3β reduces tau hyperphosphorylation, restricts the formation of neurofibrillary tangles, and restores heterochromatin loss to the physiological level. Our subsequent investigations revealed that dmyc regulates gsk3β via protein phosphatase 2A (dPP2A) in a dose-dependent manner to regulate tau pathogenesis. We propose that dmyc and gsk3β candidates can be utilized in a synergistic manner for the development of an efficient combinatorial therapeutic approach against the devastating human tauopathies.

中文翻译：

---

dMyc 下游的毛茸茸功能及其同时的下调赋予对果蝇 tau 毒性的附加拯救

诸如阿尔茨海默病和帕金森病之类的神经退行性 tau 病的特征在于 tau 蛋白的过度磷酸化以及它们随后在大脑特定区域以成对螺旋丝和/或神经原纤维缠结的形式聚集。尽管进行了多次尝试，但开发可靠的生物标志物或针对 tauopathies 的有效药物仍然是一个挑战。现在越来越明显的是，由于受致病性 tau 分子影响的多个细胞级联反应的参与，单个遗传修饰剂或分子不太可​​能有效地提供包容性的拯救。因此，已建议基于多目标的组合方法提供针对 tauopathies 的有效救援。我们之前曾报道过有针对性地下调dmyc（一种人cmyc原癌基因的果蝇同源物）通过限制 tau 过度磷酸化和异染色质丢失来限制 tau 病因。虽然，dmyc产生了重大的拯救；然而，它不足以完全缓解 tauopathies。在这里，我们报告了dmyc和gsk3β 的组织特异性并发下调传达了对果蝇中 tau 毒性的近乎完全的拯救。我们注意到dmyc和gsk3β 的组合下调减少 tau 过度磷酸化，限制神经原纤维缠结的形成，并将异染色质损失恢复到生理水平。我们随后的调查显示，dmyc调控对GSK3β通过蛋白磷酸酶以剂量依赖的方式2A（dPP2A）来调节tau蛋白病。我们建议dmyc和gsk3β候选物可以以协同方式用于开发针对破坏性人类tauopathies的有效组合治疗方法。