BACKGROUND Pallido-ponto-nigral degeneration (PPND), a major subtype of frontotemporal dementia with parkinsonism related to chromosome 17 (FTDP-17), is a progressive and terminal neurodegenerative disease caused by c.837 T > G mutation in the MAPT gene encoding microtubule-associated protein tau (rs63750756; N279K). This MAPT mutation induces alternative splicing of exon 10, resulting in a modification of microtubule-binding region of tau. Although mutations in the MAPT gene have been linked to multiple tauopathies including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, knowledge regarding how tau N279K mutation causes PPND/FTDP-17 is limited. RESULTS We investigated the underlying disease mechanism associated with the N279K tau mutation using PPND/FTDP-17 patient-derived induced pluripotent stem cells (iPSCs) and autopsy brains. In iPSC-derived neural stem cells (NSCs), the N279K tau mutation induced an increased ratio of 4-repeat to 3-repeat tau and accumulation of stress granules indicating elevated cellular stress. More significant, NSCs derived from patients with the N279K tau mutation displayed impaired endocytic trafficking as evidenced by accumulation of endosomes and exosomes, and a reduction of lysosomes. Since there were no significant differences in cellular stress and distribution of subcellular organelles between control and N279K skin fibroblasts, N279K-related vesicle trafficking defects are likely specific to the neuronal lineage. Consistently, the levels of intracellular/luminal vesicle and exosome marker flotillin-1 were significantly increased in frontal and temporal cortices of PPND/FTDP-17 patients with the N279K tau mutation, events that were not seen in the occipital cortex which is the most spared cortical region in the patients. CONCLUSION Together, our results demonstrate that alterations of intracellular vesicle trafficking in NSCs/neurons likely contribute to neurodegeneration as an important disease mechanism underlying the N279K tau mutation in PPND/FTDP-17.

中文翻译：

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额颞痴呆相关的N279K tau突变体破坏了亚细胞囊泡运输，并诱导了iPSC衍生的神经干细胞的细胞应激。

背景Pallido-ponto-negral变性（PPND）是额叶颞痴呆的主要亚型，与17号染色​​体有关的帕金森氏症（FTDP-17），是由MAPT基因编码中的c.837 T> G突变引起的进行性和终末性神经退行性疾病微管相关蛋白tau（rs63750756; N279K）。该MAPT突变诱导外显子10的选择性剪接，导致tau微管结合区的修饰。尽管MAPT基因中的突变与多种疾病相关，包括阿尔茨海默氏病，额颞痴呆和进行性核上性麻痹，但关于tau N279K突变如何引起PPND / FTDP-17的知识仍然有限。结果我们调查了使用PPND / FTDP-17患者来源的诱导多能干细胞（iPSC）和尸检大脑与N279K tau突变相关的潜在疾病机制。在iPSC衍生的神经干细胞（NSC）中，N279K tau突变诱导4重复与3重复tau的比率增加，并且应激颗粒的积累表明细胞应激增加。更重要的是，源自N279K tau突变患者的NSC显示出内吞运输受损，这由内体和外来体的积累以及溶酶体的减少所证明。由于对照组和N279K皮肤成纤维细胞之间的细胞应激和亚细胞器分布没有显着差异，因此N279K相关的囊泡运输缺陷可能是神经元谱系特有的。一致地，在N279K tau突变的PPND / FTDP-17患者的额皮质和颞皮质中，细胞内/腔囊泡和外泌体标记flotillin-1的水平显着增加，而枕骨皮质是保留最多的皮质区域中未发现的事件在病人身上。结论在一起，我们的结果表明，NSCs /神经元细胞内小泡运输的改变可能导致神经退行性变，作为PPND / FTDP-17中N279K tau突变的重要疾病机制。