O'Day Danton H
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
Biomolecules. 2025 Aug 6;15(8):1133. doi: 10.3390/biom15081133.
Tauopathies are a diverse group of neurodegenerative diseases characterized by the presence of Tau inclusions in neurons and glia. Rather than the classic steps in the transformation of Tau into neurofibrillary tangles, as first studied in Alzheimer's disease, studies on tauopathies reveal the presence of diverse Tau aggregates that appear to be disease-specific. Regardless, the phosphorylation and hyperphosphorylation of Tau, involving various kinases and phosphatases, appear to be central to all tauopathies. As in other neurodegenerative diseases, calcium dysregulation is an early event in multiple tauopathies, where it activates calmodulin to effect downstream events. Here, the events of Tau phosphorylation and hyperphosphorylation, which involve several CaM-dependent kinases and a single CaM-regulated phosphatase, are covered. In addition, CaM has been linked to other events, including Tau aggregation. As a central player in tauopathies, CaM offers several alternative therapeutic routes that are worth investigating. For example, evidence is presented here that supports targeting specific binding motifs of key CaM-regulated Tau kinases as a novel therapeutic approach.
tau蛋白病是一类多样的神经退行性疾病，其特征是神经元和神经胶质细胞中存在tau蛋白包涵体。与最初在阿尔茨海默病中研究的tau蛋白转化为神经原纤维缠结的经典步骤不同，对tau蛋白病的研究揭示了存在多种似乎具有疾病特异性的tau蛋白聚集体。尽管如此，tau蛋白的磷酸化和过度磷酸化，涉及各种激酶和磷酸酶，似乎是所有tau蛋白病的核心。与其他神经退行性疾病一样，钙调节异常是多种tau蛋白病的早期事件，它激活钙调蛋白以影响下游事件。在此，将涵盖涉及几种钙调蛋白依赖性激酶和一种钙调蛋白调节磷酸酶的tau蛋白磷酸化和过度磷酸化事件。此外，钙调蛋白还与其他事件有关，包括tau蛋白聚集。作为tau蛋白病的核心参与者，钙调蛋白提供了几种值得研究的替代治疗途径。例如，这里提供的证据支持将关键的钙调蛋白调节的tau蛋白激酶的特定结合基序作为一种新的治疗方法。
