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- W2897253308 abstract "Several mutations in the tau gene cause inherited tauopathies collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Despite the high levels of neurotoxicity these FTDP-17 mutants cause in humans and models of tauopathy, the mechanisms of toxicity are unknown. Previously, we showed that conformation changes in pathological tau activate a protein phosphatase 1 (PP1) and GSK3β signaling cascade that causes axonal transport disruptions in the squid axoplasm. However, it remained unclear whether activation of this pathway was altered by FTDP-17 mutant tau proteins. We hypothesized that FTDP-17 mutations augmented the tau-PP1 interaction and activation of PP1. Here, we used wild-type tau (WT) and three FTDP-17 mutant proteins (P301L, R5L, and Δ144-273), as well as the three PP1 isoforms (α, β, γ) in pulldown assays and bioluminescence resonance energy transfer (BRET) assays to detect protein-protein interactions. We also used phosphatase activity assays to examine the effects of tau on PP1 enzymatic activity in vitro and from mammalian cell lysates. We found that tau directly interacts with all isoforms of PP1. Interestingly, P301L displayed significantly enhanced interaction with PP1 compared to WT tau or the other two mutants. We also found that tau enhances PP1 phosphatase activity but with no significant differences in effect among WT and FTDP-17 mutant versions of tau that were tested. The results presented here support a direct interaction between tau and PP1 that can enhance phosphatase activity. This supports our hypothesis that tau can activate PP1, which may have direct implications in tau-mediated axonal transport disruption and suggests some FTDP-17 mutations may confer toxicity through altering tau's interaction with PP1, not through altering microtubule binding affinity and/or aggregation propensity." @default.
- W2897253308 created "2018-10-26" @default.
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- W2897253308 date "2018-07-01" @default.
- W2897253308 modified "2023-10-16" @default.
- W2897253308 title "P3‐181: THE INTERACTION BETWEEN TAU AND PROTEIN PHOSPHATASE 1 IS AFFECTED BY P301L MUTATION" @default.
- W2897253308 doi "https://doi.org/10.1016/j.jalz.2018.06.1539" @default.
- W2897253308 hasPublicationYear "2018" @default.
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