539-CRISPR Screens Reveal Neuronal Tau Proteostasis

Paper Talk · Feb 22, 2026 · 18m

This research paper details a large-scale CRISPR screening study conducted in human iPSC-derived neurons to identify genes that regulate tau protein levels and aggregation. The authors discovered that the CUL5-ARIH2 ubiquitin ligase complex plays a critical role in marking tau for degradation, while oxidative stress and mitochondrial dysfunction trigger the formation of a toxic 25-kDa tau fragment. Through biochemical analysis, they demonstrate that reactive oxygen species impair proteasome efficiency, leading to the accumulation of these fragments which are prone to forming tau oligomers…