Proteolysis of tau by granzyme A in tauopathies generates fragments that are aggregation prone Article Swipe
James P. Quinn
,
Kate Fisher
,
Nicola J. Corbett
,
Stacey Warwood
,
David Knight
,
Katherine A. B. Kellett
,
Nigel M. Hooper
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1042/bcj20240007
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1042/bcj20240007
Tauopathies, including Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, are characterised by the aggregation of tau into insoluble neurofibrillary tangles in the brain. Tau is subject to a range of post-translational modifications, including proteolysis, that can promote its aggregation. Neuroinflammation is a hallmark of tauopathies and evidence is growing for a role of CD8+ T cells in disease pathogenesis. CD8+ T cells release granzyme proteases but what role these proteases play in neuronal dysfunction is currently lacking. Here, we identified that granzyme A (GzmA) is present in brain tissue and proteolytically cleaves tau. Mass spectrometric analysis of tau fragments produced on digestion of tau with GzmA identified three cleavage sites at R194-S195, R209-S210 and K240-S241. Mutation of the critical Arg or Lys residues at the cleavage sites in tau or chemical inhibition of GzmA blocked the proteolysis of tau by GzmA. Development of a semi-targeted mass spectrometry approach identified peptides in tauopathy brain tissue corresponding to proteolysis by GzmA at R209-S210 and K240-S241 in tau. When expressed in cells the GzmA-cleaved C-terminal fragments of tau were highly phosphorylated and aggregated upon incubation of the cells with tauopathy brain seed. The C-terminal fragment tau195–441 was able to transfer between cells and promote aggregation of tau in acceptor cells, indicating the propensity for such tau fragments to propagate between cells. Collectively, these results raise the possibility that GzmA, released from infiltrating cytotoxic CD8+ T cells, proteolytically cleaves tau into fragments that may contribute to its pathological properties in tauopathies.
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Metadata
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- article
- Language
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- Landing Page
- https://doi.org/10.1042/bcj20240007
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All OpenAlex metadata
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https://openalex.org/W4402369996Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1042/bcj20240007Digital Object Identifier
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Proteolysis of tau by granzyme A in tauopathies generates fragments that are aggregation proneWork title
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articleOpenAlex work type
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enPrimary language
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2024Year of publication
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2024-09-09Full publication date if available
- Authors
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James P. Quinn, Kate Fisher, Nicola J. Corbett, Stacey Warwood, David Knight, Katherine A. B. Kellett, Nigel M. HooperList of authors in order
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https://doi.org/10.1042/bcj20240007Publisher landing page
- Open access
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YesWhether a free full text is available
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hybridOpen access status per OpenAlex
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https://doi.org/10.1042/bcj20240007Direct OA link when available
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Proteolysis, Chemistry, Biochemistry, Biology, Cell biology, Molecular biology, EnzymeTop concepts (fields/topics) attached by OpenAlex
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2Total citation count in OpenAlex
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2025: 2Per-year citation counts (last 5 years)
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10Other works algorithmically related by OpenAlex
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