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• W2897797990 abstract "In many different types of dementia, classified as tauopathies, the microtubule-associated protein tau is post-translationally modified. One such modification, proteolysis, causes the production of fragments of tau. The pattern of tau fragments in the brain, cerebrospinal fluid and plasma of patients with tauopathies appear to be tauopathy-specific. Here we have investigated the protease responsible for the production of a tauopathy-specific C-terminal fragment of tau, the mechanisms of its production and its potential role in tauopathy progression. Proteases predicted from the MEROPS database that could cleave tau in a region known to produce a tauopathy-specific C-terminal tau fragment, were tested with in vitro assays using recombinant proteins and analysed by gel electrophoresis, western blotting with epitope-specific antibodies and mass spectrometry. The protease and tau were transfected into HEK-293 cells to see if these cleavage events can take place intracellularly. Site-directed mutagenesis was used to block the cleavage sites. These tau fragments were subcloned and expressed in HEK-293 and NB7 cells to analyse mechanisms of secretion. We employed established high-content fluorescence microscopy assays to investigate the trans-cellular spreading and seeding aggregation propensity of the granzyme A-cleaved tau fragments. The MEROPS database showed that the novel programmed cell death activating protease granzyme A is a likely candidate for the proteolytic cleavage of tau into this tauopathy-specific fragment. Recombinant and cell transfection assays showed that granzyme A cleaves tau into 32 and 35kDa C-terminal fragments and a 37kDa N-terminal fragment. Mass spectrometry identified that tau was cleaved by granzyme A at R194-S195 and R209-S210 to produce these fragments; this was confirmed by mutating both R194 and R209 to Q, preventing cleavage. Granzyme A-cleaved tau fragments are actively secreted in a mechanism not dependent on microvesicles such as exosomes. The propensity of granzyme A-cleaved tau fragments to transcellularly spread and seed aggregation is still under investigation. Our results show that granzyme A cleaves tau to produce both N- and C-terminal fragments which likely correspond to tauopathy-specific fragments. Further work is ongoing to investigate the downstream effects of these granzyme A-cleaved tau fragments and if they are present in the brain during dementia pathogenesis." @default.
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• W2897797990 date "2018-07-01" @default.
• W2897797990 modified "2023-10-16" @default.
• W2897797990 title "O1‐06‐06: PROTEOLYTIC CLEAVAGE OF TAU IN DEMENTIA PATHOGENESIS" @default.
• W2897797990 doi "https://doi.org/10.1016/j.jalz.2018.06.2365" @default.
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