Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Cell Rep. 2022 Aug 23;40(8):111249. doi: 10.1016/j.celrep.2022.111249.
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.
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 病中，tau 被发现过度磷酸化并聚集在神经纤维缠结中。为了更好地了解启动 tau 发病机制的细胞扰动，我们进行了 CRISPR-Cas9 筛选，以寻找增强 tau 聚集的遗传修饰物。该初步筛选产生了三个基因，BANF1、ANKLE2 和 PPP2CA，其失活促进了磷酸化和不溶性 tau 的积累。在互补筛选中，我们鉴定了另外三个基因，LEMD2、LEMD3 和 CHMP7，当过度表达时，它们提供了对 tau 聚集的保护。鉴定的基因编码的蛋白在机制上相互关联，并因其在核膜维持和修复中的作用而得到认可。这些结果表明核膜完整性的破坏可能是 tau 病的一个起始事件，并揭示了治疗干预的靶点。
