Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models

• 成果类型: Article
• 署名作者: Mukadam, Aamir S.; Miller, Lauren V. C.; Smith, Annabel E.; Vaysburd, Marina; Sakya, Siri A.; Sanford, Sophie; Keeling, Sophie; Tuck, Benjamin J.; Katsinelos, Taxiarchis; Green, Chris; Skov, Lise; Kaalund, Sanne S.; Foss, Stian; Mayes, Keith; 'Connell, Kevin; Wing, Mark; Knox, Claire; Banbury, Jessica; Avezov, Edward; Rowe, James B.; Goedert, Michel; Andersen, Jan Terje; James, Leo C.; McEwan, William A.
• 署名单位: University of Cambridge; MRC Laboratory Molecular Biology; University of Oslo; University of Oslo; National Hospital Norway; University of Oslo; University of Oslo; University of Oslo; University of Cambridge; University of Copenhagen; Bispebjerg Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9700
• DOI: 10.1126/science.abn1366
• 发表日期: 2023-03-31
• 页码: 1336-+
• 关键词: human p301s tau; pathological tau; neurodegeneration; internalization; neurons; neutralization; clearance

摘要

Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but the mechanisms of Ab protection are incompletely understood. In this work, we used a variety of cell and animal model systems and showed that the cytosolic Ab receptor and E3 ligase TRIM21 (T21) could play a role in Ab protection against tau pathology. Tau-Ab complexes were internalized to the cytosol of neurons, which enabled T21 engagement and protection against seeded aggregation. Ab-mediated protection against tau pathology was lost in mice that lacked T21. Thus, the cytosolic compartment provides a site of immunotherapeutic protection, which may help in the design of Ab-based therapies in neurodegenerative disease.