Workshop 4
Workshop 4
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工作坊4
DOI：
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
L. Ittner
中科院分区：
文献类型：
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作者：
J. Götz;L. Ittner
轴突运输受损已被认为是神经退行性疾病如阿尔茨海默病（AD）的病理机制。人类的轴突长度超过一米，而且神经元通常不会更新，因此这些细胞非常容易受到运输机制的任何干扰，这并不奇怪。细胞内转运主要通过微管依赖性运输实现。微管由tau等蛋白质以及a和b-微管蛋白的异二聚体组装而成。氧化应激在AD中也有作用。由于神经元的功能依赖于线粒体向神经末梢的转运，并且由于线粒体是活性氧产生的主要位点，因此AD中的轴突转运和氧化应激假说紧密相关。转基因模型在解剖病理机制中是有用的（Götz和Ittner，Nat. Rev. Neurosci. 9：532-544，2008）。我们最初通过在转基因小鼠中表达野生型人tau来解决tau在轴突运输中的作用，所述转基因小鼠引起含有细胞骨架元件和线粒体的轴突球状体的形成（Probst et al.，神经病理学学报（柏林）。99：469-481，2008）。最近，我们表达了tau的不同突变形式，包括K369 I tau（在Picks病中发现的突变），其引起记忆障碍和帕金森综合征，沿着线粒体的轴突运输受损，接头蛋白Jip 1和含酪氨酸羟化酶（TH）的囊泡（Ittner et al.，Proc. Natl. Acad. Sci. U. S. A. 105：15997-16002，2000）。总之，这证明了tau在发病机制中的核心作用。
Impaired axonal transport has been proposed as a pathomechanism in neurodegenerative diseases such as Alzheimer’s disease (AD). With axons in humans exceeding a meter in length, and as neurons are generally not renewed, it is not surprising that these cells are highly vulnerable to any perturbation of the transport machinery. Intracellular transport is mainly achieved by microtubule-dependent trafficking. Microtubules are assembled from proteins such as tau, and heterodimers of aand b-tubulin. A role for oxidative stress has also been suggested in AD. As the functioning of a neuron is dependent on the transport of mitochondria to the nerve terminal, and as mitochondria are the primary site of the production of reactive oxygen species, the axonal transport and oxidative stress hypothesis in AD are tightly linked. Transgenic models have been instrumental in dissecting pathomechanims (Götz and Ittner, Nat. Rev. Neurosci. 9: 532–544, 2008). We addressed the role of tau in axonal transport initially by expressing wild-type human tau in transgenic mice which caused the formation of axonal spheroids containing cytoskeletal elements and mitochondria (Probst et al., Acta Neuropathol (Berl). 99: 469–481, 2008). More recently, we expressed different mutant forms of tau including K369I tau (a mutation found in Picks disease) which caused memory impairment and parkinsonism, along with timpaired axonal transport of mitochondria, the adaptor protein Jip1 and tyrosine hydroxylase (TH)-containing vesicles (Ittner et al., Proc. Natl. Acad. Sci.U.S.A. 105: 15997–16002, 2000). Together this demonstrates a central role of tau in pathogenesis.