Editors' ChoiceNeurodegeneration

Harnessing innate immunity to fight neurodegeneration

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Science Signaling  24 Jan 2017:
Vol. 10, Issue 463, eaam8102
DOI: 10.1126/scisignal.aam8102

TRIM21 prevents antibody-bound tau proteins from aggregating in cells.

Tripartite motif protein 21 (TRIM21) is a cytoplasmic receptor that mediates an innate immune response to pathogens by binding to antibody-coated pathogens that are transported into the cell rather than directly to the pathogens themselves. McEwan et al. investigated whether TRIM21 could be used to target tau protein aggregates, which are associated with neurodegenerative disorders such as Alzheimer’s disease. When the tau protein is misfolded, it forms hyperphosphorylated aggregates in the cytoplasm of neurons. Short fibrils of misfolded tau spread between cells, inducing or “seeding” tau aggregation throughout the brain. To demonstrate that TRIM21 was active in neural cells, the authors incubated neural cell cultures with adenovirus in the presence or absence of an antibody. Antibody-coated viruses infected the cells less efficiently than did antibody-free viruses, particularly when the cells were stimulated with type I or type II interferons. Protection from infection correlated with the abundance of Trim21 mRNA, suggesting that TRIM21 was functional in neurons. To evaluate whether TRIM21 targeted tau seeds, the authors developed a microscopy-based assay to detect fluorescently tagged tau protein in transfected HEK 293 cells. Adding purified recombinant tau seeds to the cells induced tau protein aggregation, as did the addition of tau protein from brain tissue samples of Alzheimer’s disease patients. Several antibodies against tau were then identified that prevented tau seeds from inducing aggregation in this assay. In cells in which TRIM21 was knocked down by CRISPR/Cas, the extent of tau seeding in the presence of the antibodies was as great as that in their absence. TRIM21 leads to the elimination of antibody-bound pathogens by stimulating their destruction by proteasomes and the unfoldase valosin-containing protein (VCP). Experiments with pharmacological inhibitors showed that these cofactors were also required for the degradation of antibody-bound tau. However, inhibiting the proteasome only partially blocked antibody-dependent prevention of tau aggregation, whereas inhibiting VCP had a more substantial effect, suggesting that unfolding the tau seed might be a critical step in preventing aggregation. Together, these results suggest that the TRIM21-dependent immune response could be co-opted to treat neurodegenerative disorders caused by protein aggregates.

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