Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.
Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1.
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DOI：
10.1371/journal.pgen.1002918
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Iijima KM
中科院分区：
文献类型：
--
作者：
Iijima-Ando K;Sekiya M;Maruko-Otake A;Ohtake Y;Suzuki E;Lu B;Iijima KM
微管相关蛋白tau的异常磷酸化和毒性参与了阿尔茨海默病(AD)的发病机制，然而，什么病理条件在AD中引发tau异常还不完全清楚。轴突中线粒体数量的减少与AD有关。在这项研究中，我们研究了轴突线粒体的丢失是否以及如何在体内促进tau的磷酸化和毒性。利用表达人tau的转基因果蝇，我们发现RNAi介导的Milton或Miro的敲除，一个线粒体轴突运输所必需的接头蛋白，增强了tau诱导的神经变性。AD相关位点Ser262的tau磷酸化水平随着Milton或Miro基因的敲除而增加；而哺乳动物微管亲和力调节激酶的同源物果蝇缺陷1(PAR-1)的分割介导了tau磷酸化的增加。据报道，tau在Ser262位发生磷酸化，促进tau从微管中脱离，我们发现Milton基因敲除后，微管游离tau的水平增加。通过PAR-1基因敲除Ser262位的tau磷酸化，或将Ser262位突变为不可磷酸化的丙氨酸，可抑制由Milton基因敲除引起的tau诱导的神经变性的增强。此外，米尔顿或米罗的基因敲除增加了活性PAR-1的水平。这些结果表明，在轴突线粒体耗尽的病理条件下，通过PAR-1增加tau在Ser262位的磷酸化有助于tau介导的神经变性。有趣的是，我们发现，单独敲除Milton或Miro会导致果蝇大脑中迟发性的神经退化，这种神经退化可以通过敲除果蝇tau或PAR-1来抑制。我们的结果提示轴突线粒体的丢失可能在tau的磷酸化和毒性中起重要作用。微管相关蛋白tau的异常磷酸化和毒性参与了阿尔茨海默病(AD)的发病。Tau在多个位点被磷酸化，并且tau的磷酸化调节其微管结合和生理功能，如调节微管稳定性。Tau的异常磷酸化发生在AD的大脑中，被认为是导致tau毒性的原因；然而，什么病理条件在AD中引发tau的异常磷酸化和毒性还不完全清楚。由于在AD脑中观察到轴突中线粒体数量的减少，我们研究了轴突线粒体的丢失是否以及如何促进tau的磷酸化和毒性。利用表达人tau的转基因果蝇，我们发现，敲除Milton或Miro，线粒体轴突运输所必需的适配器蛋白，增强了tau诱导的神经退化。这项研究表明，Milton基因敲除导致的轴突线粒体丢失通过分割缺陷-1(PAR-1)增加了AD相关部位tau的磷酸化，促进了tau从微管中分离，并加强了tau介导的神经变性。我们的结果提示轴突线粒体的丢失可能在tau的磷酸化和毒性中起重要作用。
Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi–mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD–related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. These results suggest that an increase in tau phosphorylation at Ser262 through PAR-1 contributes to tau-mediated neurodegeneration under a pathological condition in which axonal mitochondria is depleted. Intriguingly, we found that knockdown of milton or Miro alone caused late-onset neurodegeneration in the fly brain, and this neurodegeneration could be suppressed by knockdown of Drosophila tau or PAR-1. Our results suggest that loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD. Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD). Tau is phosphorylated at multiple sites, and phosphorylation of tau regulates its microtubule binding and physiological functions such as regulation of microtubule stability. Abnormal phosphorylation of tau occurs in the AD brains and is thought to cause tau toxicity; however, what pathological conditions trigger abnormal phosphorylation and toxicity of tau in AD is not fully understood. Since a reduction in the number of mitochondria in the axon has been observed in the AD brains, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity. Using transgenic flies expressing human tau, we found that knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. This study demonstrates that loss of axonal mitochondria caused by milton knockdown increases tau phosphorylation at an AD–related site through partitioning defective-1 (PAR-1), promotes detachment of tau from microtubules, and enhances tau-mediated neurodegeneration. Our results suggest that loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD.
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依赖性β-淀粉样蛋白引发的tau依赖性微管拆卸。
DOI：
10.1083/jcb.200605187
发表时间：
2006-11-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
King ME;Kan HM;Baas PW;Erisir A;Glabe CG;Bloom GS
通讯作者：
Bloom GS
DOI：
10.1083/jcb.200601067
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glater EE;Megeath LJ;Stowers RS;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
4.8
作者：
DREWES, G;TRINCZEK, B;MANDELKOW, E
通讯作者：
MANDELKOW, E
影响因子：
9.2
作者：
Fang, Yanshan;Soares, Lorena;Teng, Xiuyin;Geary, Melissa;Bonini, Nancy M
通讯作者：
Bonini, Nancy M
影响因子：
3.5
作者：
Iijima-Ando, Kanae;Zhao, LiJuan;Iijima, Koichi
通讯作者：
Iijima, Koichi