CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.

Avi J Samelson, Nabeela Ariqat, Justin McKetney, Gita Rohanitazangi, Celeste Parra Bravo, Rudra Bose, Kyle J Travaglini, Victor L Lam, Darrin Goodness, Gary Dixon, Emily Marzette, Julianne Jin, Ruilin Tian, Eric Tse, Romany Abskharon, Henry Pan, Emma C Carroll, Rosalie E Lawrence, Jason E Gestwicki, David Eisenberg, Nicholas M Kanaan, Daniel R Southworth, John D Gross, Li Gan, Danielle L Swaney, Martin Kampmann
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Abstract

Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation and subsequent dysfunction and death, but the underlying mechanisms are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways, including UFMylation and GPI anchor synthesis. We discover that the E3 ubiquitin ligase CUL5SOCS4 is a potent modifier of tau levels in human neurons, ubiquitinates tau, and is a correlated with vulnerability to tauopathies in mouse and human. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, which generates tau proteolytic fragments like those in disease and changes tau aggregation in vitro. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

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iPSC衍生神经元的CRISPR筛选揭示了tau蛋白稳定的原理。
与年龄相关的神经退行性疾病的一个标志是蛋白质的聚集。tau蛋白的聚集定义了tau病,包括阿尔茨海默病和额颞叶痴呆。特定的神经元亚型选择性地易受tau聚集体积累以及随后的功能障碍和死亡的影响。细胞类型选择性脆弱性的潜在机制尚不清楚。为了系统地揭示控制人类神经元中tau聚集体积累的细胞因子,我们在iPSC衍生的神经元中进行了全基因组CRISPRi修饰物筛选。该筛选揭示了预期的途径,包括自噬,但也揭示了控制tau寡聚物水平的意外途径,包括UFMylation和GPI锚合成。我们将E3泛素连接酶CUL5鉴定为tau相互作用因子和tau水平的有效调节剂。此外,线粒体功能的破坏增加了tau寡聚物的水平,并促进了蛋白酶体对tau的错误处理。这些结果揭示了人类神经元中tau蛋白稳定的新原理,并确定了tau病的潜在治疗靶点。
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