Hyperphosphorylation and aggregation of the microtubule-binding protein tau characterize a diverse array of neurodegenerative disorders. Most of these lack mutations in the encoding MAPT gene, and the role of tau in disease pathogenesis remains controversial. Among these tauopathies is Niemann-Pick type C disease (NPC), a lysosomal storage disorder characterized by progressive neurodegeneration and premature death, most often caused by an inherited deficiency in the intracellular lipid trafficking protein NPC1. To determine the extent to which tau affects NPC pathogenesis, we generated Npc1-/- mice deficient in tau. Unexpectedly, NPC1/tau double null mutants are generated in markedly smaller litters, exhibit an enhanced systemic phenotype and die significantly earlier than NPC1 single null mutants. As autophagy is up-regulated in NPC and protein degradation through this pathway depends on movement along microtubules, we knocked down MAPT expression in NPC1-deficient human fibroblasts and examined effects on this pathway. We show that an acute reduction of tau expression in a cellular model of NPC decreases induction and flux through the autophagic pathway. Our data establish that MAPT deletion exacerbates the NPC phenotype through a mechanism independent of tau protein aggregation and identifies a critical role for tau in the regulation of autophagy in NPC1-deficient cells.

译文

微管结合蛋白tau的过度磷酸化和聚集表征了多种神经退行性疾病。其中大多数缺乏编码MAPT基因的突变,tau在疾病发病机制中的作用仍存在争议。在这些tau病中,有尼曼-皮克C型疾病 (NPC),这是一种溶酶体贮积障碍,其特征是进行性神经变性和过早死亡,通常是由细胞内脂质运输蛋白npc1的遗传缺陷引起的。为了确定tau对NPC发病机理的影响程度,我们生成了缺乏tau的Npc1-/-小鼠。出乎意料的是,NPC1/tau双空突变体在明显较小的凋零中生成,表现出增强的系统表型,并且比NPC1单个空突变体明显更早死亡。由于自噬在NPC中被上调,并且通过该途径的蛋白质降解取决于沿微管的运动,因此我们下调了NPC1-deficient人成纤维细胞中的MAPT表达,并检查了对该途径的影响。我们显示,NPC细胞模型中tau表达的急剧降低会降低自噬途径的诱导和通量。我们的数据表明,MAPT缺失通过独立于tau蛋白聚集的机制加剧了NPC表型,并确定了tau在NPC1-deficient细胞自噬调节中的关键作用。

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