tau 蛋白向树突棘的定位错误介导了突触功能障碍，而与神经退行性变无关。
Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration.
机构信息
Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA.
出版信息
Neuron. 2010 Dec 22;68(6):1067-81. doi: 10.1016/j.neuron.2010.11.030.
The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.
微管相关蛋白 tau 在阿尔茨海默病和其他致命性痴呆症中积累，这些病症在大脑前神经元死亡时表现出来。最近对这些疾病的理解进展表明，脑功能障碍先于神经退行性变，但 tau 的作用尚不清楚。在这里，我们表明，tau 相关的早期缺陷不是由于突触或神经元的丧失，而是由于在完整的树突棘内积累的过度磷酸化 tau 引起的突触异常所致，tau 通过损害谷氨酸受体运输或突触锚定来破坏突触功能。通过将 14 个与疾病相关的丝氨酸和苏氨酸氨基酸残基突变为假超磷酸化 tau，导致 tau 定位错误，而创建磷酸化缺陷的 tau 阻止了 tau 错误靶向到树突棘。因此，tau 磷酸化在介导 tau 定位错误和随后的突触损伤中起着关键作用。这些数据表明，tau 引起的早期突触功能障碍的位置位于树突棘中。
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