一部の神経細胞がアルツハイマー病に耐性を示す理由を解明(Why some brain cells resist Alzheimer’s disease)

2026-02-05 カリフォルニア大学ロサンゼルス校(UCLA)

<関連情報>

• https://newsroom.ucla.edu/releases/scientists-uncover-why-some-brain-cells-resist-alzheimers-disease
• https://www.cell.com/cell/fulltext/S0092-8674(25)01487-4

iPSC由来ニューロンにおけるCRISPRスクリーニングによりタウタンパク質恒常性の原理が明らかに CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

Avi J. Samelson ∙ Nabeela Ariqat ∙ Justin McKetney ∙ … ∙ Li Gan ∙ Danielle L. Swaney ∙ Martin Kampmann
Cell  Published:January 28, 2026
DOI:https://doi.org/10.1016/j.cell.2025.12.038

Highlights

• CRISPR screens in human neurons reveal modifiers of tau oligomer accumulation
• CUL5 and the substrate-specific adaptor SOCS4 function as tau E3 ubiquitin ligase
• Expression of CUL5 complexes is correlated with resilience in tauopathies
• Reactive oxygen species generate a disease-relevant tau proteolytic fragment

Summary

Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer’s disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi screen in induced pluripotent stem cell (iPSC)-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, which control tau oligomer levels. We discovered that the E3 ubiquitin ligase CRL5^SOCS4 controls tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, generating disease-relevant tau proteolytic fragments and changing tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies.