Laboratory of Biology, BIO@SNS, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy.
Institute of Neuroscience, Italian National Research Council, Via Moruzzi 1, 56124 Pisa, Italy.
Int J Mol Sci. 2021 Sep 20;22(18):10145. doi: 10.3390/ijms221810145.
Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.
Tau 在一组被统称为 tau 病的神经退行性疾病中起着核心作用。尽管在病理学的起始和进展过程中出现了广泛的各种症状，但所有 tau 病都有两个共同的特征，即 Tau 蛋白的错误折叠和聚集以及进行性的突触功能障碍。Tau 聚集与认知能力下降和行为障碍有关。Tau 错误折叠与突触功能障碍之间的机制联系尚不清楚，但这种相关性在人类大脑和 tau 病小鼠模型中得到了很好的证实。在病理学的起始阶段，Tau 经历了翻译后修饰（PTMs），导致其从细胞骨架上脱离并以可溶性单体的形式释放到细胞质中。在这种情况下，轴突中的生理富集肯定会被打乱，导致 Tau 在细胞体和树突中重新定位。随后，Tau 聚集形成毒性寡聚物和淀粉样形成物，破坏突触的稳态和功能，导致神经元变性。Tau 在 tau 病中突触传递改变的作用已经被广泛综述。在这里，我们将重点关注介导突触功能障碍的非典型 Tau 功能。
