Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.
Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.
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DOI：
10.1016/j.nbd.2015.10.007
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发表时间：
2016-01
影响因子：
6.1
通讯作者：
Hanger DP
中科院分区：
文献类型：
--
作者：
Rodríguez-Martín T;Pooler AM;Lau DHW;Mórotz GM;De Vos KJ;Gilley J;Coleman MP;Hanger DP
额颞叶痴呆相关的tau突变P301L在成年小鼠脑(Ki-P301L小鼠)生理水平的表达导致tau明显的低磷酸化和周围神经轴突线粒体运输的年龄依赖性改变。为了确定P301L tau在中枢神经系统中的表达，我们检测了P301L基因敲除小鼠(Ki-P301L)原代皮层神经元线粒体轴突转运和tau磷酸化的动力学。我们观察到，与野生型神经元相比，Ki-P301L小鼠培养的皮质神经元轴突中的线粒体数量显着减少了50%。小鼠P301L tau的表达不改变线粒体的速度、移动方向或移动的可能性。值得注意的是，在表达P301L tau的神经元中，定义轴突中线粒体方向的角度和单个运动线粒体的体积显著增加。我们发现，与野生型神经元相比，KI-P301L小鼠神经元中小鼠tau的磷酸化程度降低，并且P301L tau与微管的结合能力也降低。P301L突变不影响小鼠tau与皮层神经元或成年小鼠脑内细胞膜的结合能力。我们的结论是，P301L tau与线粒体的改变有关，并导致小鼠神经元tau磷酸化的早期降低，并伴随tau微管结合的受损。这些结果支持突变的tau与对线粒体的有害影响有关，并将对tau病的发病机制具有重要意义。P301L tau的表达减少了小鼠轴突线粒体的数量。P301L tau组神经元轴突内运动性线粒体体积增大。在敲门小鼠中表达的P301L tau是低磷酸化的。P301L tau突变损害微管结合，但不影响tau膜定位。
Expression of the frontotemporal dementia-related tau mutation, P301L, at physiological levels in adult mouse brain (KI-P301L mice) results in overt hypophosphorylation of tau and age-dependent alterations in axonal mitochondrial transport in peripheral nerves. To determine the effects of P301L tau expression in the central nervous system, we examined the kinetics of mitochondrial axonal transport and tau phosphorylation in primary cortical neurons from P301L knock-in (KI-P301L) mice. We observed a significant 50% reduction in the number of mitochondria in the axons of cortical neurons cultured from KI-P301L mice compared to wild-type neurons. Expression of murine P301L tau did not change the speed, direction of travel or likelihood of movement of mitochondria. Notably, the angle that defines the orientation of the mitochondria in the axon, and the volume of individual moving mitochondria, were significantly increased in neurons expressing P301L tau. We found that murine tau phosphorylation in KI-P301L mouse neurons was diminished and the ability of P301L tau to bind to microtubules was also reduced compared to tau in wild-type neurons. The P301L mutation did not influence the ability of murine tau to associate with membranes in cortical neurons or in adult mouse brain. We conclude that P301L tau is associated with mitochondrial changes and causes an early reduction in murine tau phosphorylation in neurons coupled with impaired microtubule binding of tau. These results support the association of mutant tau with detrimental effects on mitochondria and will be of significance for the pathogenesis of tauopathies. Expression of P301L tau reduces the number of axonal mitochondria in mice. Motile mitochondria exhibit increased volume in axons of neurons with P301L tau. P301L tau expressed in knockin mice is hypophosphorylated. The P301L tau mutation impairs microtubule binding but does not affect tau membrane localization.