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• W2536272321 abstract "A key open question in the tauopathy field is how tau proteins aggregate and cause proteotoxic stress. We recently published a first in-depth tau interactome, which revealed that tau carrying the P301L frontotemporal dementia mutation exhibits reduced interactions with heat shock proteins and the proteasome (1). Our previous work captured steady-state interactions of a specific mutated and plasmid-encoded tau isoform. However, as disease evolves dynamically, critically needed are next generation models that can be induced to reveal the chronology of events underlying tau’s aggregation and proteotoxicity. We are poised to fill this unmet need with novel CRISPR/Cas9-generated cell models that can be induced to express human tau alleles. Specifically, inducible tau IMR-32 human neuroblastoma cells were created in a two-step gene engineering workflow: first, a pair of foundation lox sites was inserted into the AAVS1 human genome safe harbor locus via a CRISPR/Cas9 nickase strategy. Second, wild-type or P301L tau C-terminally fused to the enhanced green fluorescent protein were inserted into the primed AAVS1 locus via Cre recombinase-mediated heterologous gene exchange using the foundation lox sites. The system can be used for time-course transcriptome and proteome analyses. Accurate transgene insertion was confirmed by genomic PCR and sequencing. Marked induction and tight leakage control of the inducible model were validated by Western blotting after treating the cells with doxycycline for 0-18 h. A preliminary mass spectrometry analysis confirmed that tau interacts with a large segment of the cellular ribonucleoproteome and chaperones. Data collected to date establish the successful implementation of an inducible tau-EGFP expression system that will allow us to dissect the time-course of aberrant tau interactions underlying proteotoxic stress. Targeted insertion minimizes the deleterious effects of random integrations, and the flexible two-step process can potentially accommodate any genes of interest." @default.
• W2536272321 created "2016-10-28" @default.
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• W2536272321 date "2016-07-01" @default.
• W2536272321 modified "2023-09-27" @default.
• W2536272321 title "P4-290: Binding with the Wrong Partners: a CRISPR/CAS9-Edited Inducible Human Cell System Designed to Reveal the Chronology of Events Leading to Proteotoxic Stress in Tauopathies" @default.
• W2536272321 cites W2176134948 @default.
• W2536272321 doi "https://doi.org/10.1016/j.jalz.2016.07.032" @default.
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