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.
journal_name
Proc Natl Acad Sci U S Aauthors
McEwan WA,Falcon B,Vaysburd M,Clift D,Oblak AL,Ghetti B,Goedert M,James LCdoi
10.1073/pnas.1607215114subject
Has Abstractpub_date
2017-01-17 00:00:00pages
574-579issue
3eissn
0027-8424issn
1091-6490pii
1607215114journal_volume
114pub_type
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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