Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

William A. McEwan, Benjamin Falcon, Marina Vaysburd, Dean Clift, Adrian L. Oblak, Bernardino Ghetti, Michel Goedert, Leo C. James

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubuleassociated 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.

Original languageEnglish (US)
Pages (from-to)574-579
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number3
DOIs
StatePublished - Jan 17 2017

Fingerprint

Fc Receptors
Seeds
tau Proteins
Virus Diseases
Proteasome Endopeptidase Complex
Neurodegenerative Diseases
Antiviral Agents
Anti-Idiotypic Antibodies
Immunity
Alzheimer Disease
Viruses
Antibodies
Brain
Tripartite Motif Proteins
Proteins

Keywords

  • Antibodies
  • Immunoreceptors
  • Intracellular immunity
  • Neurodegeneration
  • Tau

ASJC Scopus subject areas

  • General

Cite this

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. / McEwan, William A.; Falcon, Benjamin; Vaysburd, Marina; Clift, Dean; Oblak, Adrian L.; Ghetti, Bernardino; Goedert, Michel; James, Leo C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 3, 17.01.2017, p. 574-579.

Research output: Contribution to journalArticle

McEwan, William A. ; Falcon, Benjamin ; Vaysburd, Marina ; Clift, Dean ; Oblak, Adrian L. ; Ghetti, Bernardino ; Goedert, Michel ; James, Leo C. / Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 3. pp. 574-579.
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