Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia
Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia
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DOI：
10.1073/pnas.0808084105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Goetz, Juergen
中科院分区：
文献类型：
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作者：
Ittner, Lars M.;Fath, Thomas;Goetz, Juergen
额颞叶痴呆（FTD）以认知和行为改变为特征，在很大一部分患者中，还伴有帕金森病。组织病理学上，FTD经常表现为含有tau的病变，在家族病例中，这是由编码tau的MAPT基因突变引起的。在这里，我们提出了一种新的转基因小鼠品系（K3），表达携带FTD突变K3691的人类tau。K3小鼠发展为进行性组织病理学，与K3691突变的人FTD相似。此外，K3小鼠在没有明显神经变性的情况下表现出早发性记忆障碍和肌萎缩。与我们之前产生的tau转基因菌株不同，K3小鼠在黑质（SN）中表达转基因，并表现出早发性运动表型，再现帕金森病伴震颤、运动迟缓、步态异常和姿势不稳定。有趣的是，年轻而不是年老的K3小鼠的运动表现在左旋多巴治疗后得到改善，这与帕金森病的FTD相似。K3小鼠的早发性症状在机制上与不同货物的选择性顺行轴突运输受损有关，这先于老年小鼠发生的多巴胺能SN神经元的丧失。神经元轴突转运受损影响了含有多巴胺合成酶酪氨酸羟化酶的囊泡。不同的运输方式也在坐骨神经中受损，这可能解释肌萎缩。总之，K3小鼠是ftd相关帕金森病的独特模型，对人类病理过程具有病理机制意义。
Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K3691. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K3691 mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.