German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Max-Planck-Institute for Metabolism Research, Cologne, Germany.
Adv Exp Med Biol. 2019;1184:97-103. doi: 10.1007/978-981-32-9358-8_8.
Mutations in MAPT (Tau) have been implicated in several types of tauopathy, but the pathways leading to neurodegeneration have remained elusive and are heterogeneous. Here we describe the effects of two mutations, both linked to AD or FTD, that are located in different domains of Tau and show different pathways of toxicity. The deletion mutation ΔK280 lies in the repeat domain and strongly increases β-structure and hence aggregation, whereas the mutation A152T lies in the N-terminal projection domain, has little effect on aggregation but instead on signalling. Both mutations cause presynaptic dysfunction, but in opposite ways, leading to hypoexcitability/hypoactivity vs. hyperexcitability/excitotoxicity, respectively. In organotypic slices these abnormal states can be reversed by drugs, e.g. Tau aggregation inhibitors or modulators of glutamate uptake. This information could contribute to the understanding of "normal" Tau biology and possible therapeutical strategies.
MAPT（Tau）中的突变与几种类型的 Tau 病有关，但导致神经退行性变的途径仍然难以捉摸且具有异质性。在这里，我们描述了两种突变的影响，这两种突变都与 AD 或 FTD 有关，位于 Tau 的不同结构域，并显示出不同的毒性途径。缺失突变 ΔK280 位于重复结构域，强烈增加β-结构，从而增加聚集，而突变 A152T 位于 N 端投射结构域，对聚集几乎没有影响，但对信号转导有影响。这两种突变都导致了突触前功能障碍，但方式相反，分别导致兴奋性降低/活性降低与兴奋性过高/兴奋毒性。在器官型切片中，这些异常状态可以通过药物逆转，例如 Tau 聚集抑制剂或谷氨酸摄取调节剂。这些信息可能有助于理解“正常” Tau 生物学和可能的治疗策略。
