Institute for Fundamental Biomedical Research, Biomedical Sciences Research Centre "Alexander Fleming", Vari, Greece.
Adv Exp Med Biol. 2020;1233:177-194. doi: 10.1007/978-3-030-38266-7_7.
Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation or mutations of the neuronal microtubule-binding protein Tau. Tauopathies are characterized by accumulation of hyperphosphorylated Tau leading to formation of a range of aggregates including macromolecular ensembles such as Paired Helical filaments and Neurofibrilary Tangles whose morphology characterizes and differentiates these disease states. Why nonphysiological Tau proteins elude the surveillance normal proteostatic mechanisms and eventually form these macromolecular assemblies is a central mostly unresolved question of cardinal importance for diagnoses and potential therapeutic interventions. We discuss the response of the Ubiquitin-Proteasome system, autophagy and the Endoplasmic Reticulum-Unfolded Protein response in Tauopathy models and patients, revealing interactions of components of these systems with Tau, but also of the effects of pathological Tau on these systems which eventually lead to Tau aggregation and accumulation. These interactions point to potential disease biomarkers and future potential therapeutic targets.
tau 病是一组异质性的神经退行性痴呆，涉及神经元微管结合蛋白 tau 的水平、磷酸化或突变的改变。tau 病的特征是过度磷酸化 tau 的积累，导致一系列聚集物的形成，包括高分子聚集体，如成对螺旋丝和神经原纤维缠结，其形态特征和区分这些疾病状态。为什么非生理 tau 蛋白逃避正常的蛋白质稳态机制，并最终形成这些高分子组装，这是一个核心的、尚未解决的主要问题，对于诊断和潜在的治疗干预至关重要。我们讨论了泛素-蛋白酶体系统、自噬和内质网未折叠蛋白反应在 tau 病模型和患者中的反应，揭示了这些系统的成分与 tau 的相互作用，但也揭示了病理性 tau 对这些系统的影响，这些系统最终导致 tau 聚集和积累。这些相互作用指向潜在的疾病生物标志物和未来潜在的治疗靶点。
