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

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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.



Animals, Mice, Antibodies, Monoclonal, Cytosol, Disease Models, Animal, Immunization, Passive, Receptors, Fc, Ribonucleoproteins, tau Proteins, Tauopathies, Tripartite Motif Proteins, Ubiquitin-Protein Ligases

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American Association for the Advancement of Science (AAAS)
UK Dementia Research Institute (Unknown)
Wellcome Trust (103838/Z/14/Z)
Wellcome Trust (206248/Z/17/Z)
Wellcome Trust (220258/Z/20/Z)
Wellcome Trust (206248/Z/17/A)
This study was supported by a Sir Henry Dale Fellowship to WAM jointly funded by the Wellcome Trust and the Royal Society (Grant Number 206248/Z/17/Z) and by the Lister Institute for Preventative Medicine. Further support was provided by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. ASM was partly supported by Takeda Pharmaceuticals for work unrelated to this project. This work has also received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116060 (IMPRiND). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 17.00038. BJT was supported by the Hughes Hall and Cambridge Trust PhD scholarship. SS was supported by a PhD studentship award from Alzheimer’s Society, UK (grant number AS-PhD-18b-018). LVCM was supported by UK Medical Research Council DTP PhD scholarship. CG was supported by a PhD studentship funded by Alzheimer’s Research UK (ARUK-PhD2018-051). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312). JBR is supported by the Wellcome Trust (103838; 220258). SSK was funded by the Lundbeck foundation (R232-2016-2333 and R232-2017-2333). JTA, SF and SAS were supported by the Civitan Research Fund for Alzheimer`s disease, and the Research Council of Norway (Grant no. 287927, 314909 and 335688). LCJ & MV were supported by a Welcome Trust Investigator Award to LCJ (223054/Z/21/Z) and the MRC (UK; U105181010).