微管相关蛋白tau是中枢神经系统神经元的丰富成分。在阿尔茨海默病和其他神经退行性tau病变中,发现tau过度磷酸化并聚集在神经原纤维缠结中。为了更好地了解启动tau发病机制的细胞扰动,我们对增强tau聚集的遗传修饰剂进行了CRISPR-Cas9筛选。这个初步筛选产生了三个基因,BANF1、ANKLE2和PPP2CA,其失活促进tau以磷酸化和不溶性形式的积累。在互补的屏幕中,我们确定了三个额外的基因,LEMD2、LEMD3和CHMP7,当过度表达时,防止tau聚集。由鉴定的基因编码的蛋白质在机械上联系起来,并因其在核包膜的维持和修复中的作用而得到认可。这些结果暗示核包膜完整性的破坏是tau蛋白病变中可能的起始事件,并揭示了治疗干预的靶标。
The microtubule-associated protein tau is an abundant component of neurons of the central nervous system. In Alzheimer\'s disease and other neurodegenerative tauopathies, tau is found hyperphosphorylated and aggregated in neurofibrillary tangles. To obtain a better understanding of the cellular perturbations that initiate tau pathogenesis, we performed a CRISPR-Cas9 screen for genetic modifiers that enhance tau aggregation. This initial screen yielded three genes, BANF1, ANKLE2, and PPP2CA, whose inactivation promotes the accumulation of tau in a phosphorylated and insoluble form. In a complementary screen, we identified three additional genes, LEMD2, LEMD3, and CHMP7, that, when overexpressed, provide protection against tau aggregation. The proteins encoded by the identified genes are mechanistically linked and recognized for their roles in the maintenance and repair of the nuclear envelope. These results implicate the disruption of nuclear envelope integrity as a possible initiating event in tauopathies and reveal targets for therapeutic intervention.