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Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):574-579. doi: 10.1073/pnas.1607215114. Epub 2017 Jan 3.

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation.

Author information

1
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; wmcewan@mrc-lmb.cam.ac.uk mg@mrc-lmb.cam.ac.uk lcj@mrc-lmb.cam.ac.uk.
2
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
3
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.

Abstract

Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.

KEYWORDS:

antibodies; immunoreceptors; intracellular immunity; neurodegeneration; tau

PMID:
28049840
PMCID:
PMC5255578
DOI:
10.1073/pnas.1607215114
[Indexed for MEDLINE]
Free PMC Article

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