Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons.
Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons.
复制标题
DOI：
10.1016/j.stemcr.2022.08.001
复制
发表时间：
2022-09-13
影响因子：
5.9
通讯作者：
Young-Pearse, Tracy L.
中科院分区：
文献类型：
--
作者：
Fernandez, Marty A.;Bah, Fatmata;Ma, Li;Lee, YouJin;Schmidt, Michael;Welch, Elizabeth;Morrow, Eric M.;Young-Pearse, Tracy L.
内溶酶体和自噬溶酶体系统的破坏越来越多地与神经变性有关。钠-质子交换剂6 （NHE6）有助于维持适当的内体pH值，而x连锁NHE6的功能缺失突变导致男性克里斯蒂安森综合征（CS）。CS的神经退行性特征越来越被认识到，死后和临床数据暗示了tau的作用。我们从NHE6敲除（KO）和等基因野生型对照的人诱导多能干细胞中生成皮质神经元。我们报告了NHE6 KO神经元中磷酸化和萨科齐不溶性tau蛋白的升高。我们证明NHE6 KO导致溶酶体和自噬功能障碍，包括溶酶体数量和蛋白酶活性降低，自噬通量减少和p62积累。最后，我们表明海藻糖或雷帕霉素治疗，两种自噬溶酶体功能增强剂，各部分挽救这种tau表型。我们深入研究了NHE6功能丧失背后的神经退行性过程，并深入研究了内核-溶酶体-自噬网络在神经退行性疾病中的广泛作用。NHE6突变体ipsc衍生皮质神经元表现出磷酸化tau蛋白升高NHE6突变体神经元表现出溶酶体和自噬功能障碍NHE6 KO神经元中观察到的tau表型通过增强自噬而得到拯救Fernandez等人表明，内体蛋白NHE6的缺失，导致x连锁神经发育障碍Christianson综合征的突变，导致ipsc衍生皮质神经元中与阿尔茨海默病和相关痴呆相关的tau蛋白的变化。这些神经元表现出溶酶体和自噬功能的减少，海藻糖或雷帕霉素治疗可以挽救tau的病理变化。
Disruption of endolysosomal and autophagy-lysosomal systems is increasingly implicated in neurodegeneration. Sodium-proton exchanger 6 (NHE6) contributes to the maintenance of proper endosomal pH, and loss-of function mutations in the X-linked NHE6 lead to Christianson syndrome (CS) in males. Neurodegenerative features of CS are increasingly recognized, with postmortem and clinical data implicating a role for tau. We generated cortical neurons from NHE6 knockout (KO) and isogenic wild-type control human induced pluripotent stem cells. We report elevated phosphorylated and sarkosyl-insoluble tau in NHE6 KO neurons. We demonstrate that NHE6 KO leads to lysosomal and autophagy dysfunction involving reduced lysosomal number and protease activity, diminished autophagic flux, and p62 accumulation. Finally, we show that treatment with trehalose or rapamycin, two enhancers of autophagy-lysosomal function, each partially rescue this tau phenotype. We provide insight into the neurodegenerative processes underlying NHE6 loss of function and into the broader role of the endosome-lysosome-autophagy network in neurodegeneration. NHE6 mutant iPSC-derived cortical neurons display elevated phosphorylated tau NHE6 mutant neurons exhibit lysosomal and autophagy dysfunction Tau phenotypes observed in NHE6 KO neurons are rescued by enhancing autophagy Fernandez et al. show that loss of the endosomal protein NHE6, mutations in which cause the X-linked neurodevelopmental disorder Christianson syndrome, leads to changes in tau associated with Alzheimer disease and related dementias in iPSC-derived cortical neurons. These neurons display reductions in lysosomal and autophagic function, and the pathological changes in tau are rescued by treatment with trehalose or rapamycin.
登录
查看更多内容
影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
4
作者：
Christianson, AL;Stevenson, RE;Schwartz, CE
通讯作者：
Schwartz, CE
影响因子：
5.4
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
影响因子：
5.3
作者：
Kondapalli KC;Prasad H;Rao R
通讯作者：
Rao R
影响因子：
5.4
作者：
Belzile, Jean-Philippe;Sabalza, Maite;Spector, Deborah H.
通讯作者：
Spector, Deborah H.