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Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, ParraBravo C, Goodness D, Tian R, Grosjean P, Abskharon R, Eisenberg D, Kanaan NM, Gan L, Condello C, Swaney DL, Kampmann M. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. 2023 Jun 17 10.1101/2023.06.16.545386 (version 1) bioRxiv.
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University of Texas, Southwestern Medical Center
I think this is an interesting paper. It shows the power of the screening method to pick out genes with even subtle effects on cell biology. I would need a little more data to convince me that they have truly found modifiers of tau oligomer formation/clearance.
The reliance on conformation-specific antibodies should be supplemented with biochemistry to show that the putative oligomers detected are, in fact, higher-order tau assemblies.
The biological effects are quite subtle. Even in highly controlled conditions, the knockdown of Cul5 produces a ~2x increase in signal. This is surprisingly low if this is an important regulator. It would have been helpful to compare this to knockdown/inhibition of other parts of the degradation machinery for reference. Again, the use of biochemistry to study oligomer levels would have been useful to be more convincing.
The secondary point of the paper, that oxidative stress produces tau fragments, is interesting, but the meaning is unclear to me. Without carefully comparing the identity of the fragments created by stress to those that are detected as biomarkers in patients (e.g., by using mass spectrometry) it might be a stretch to suggest that oxidative stress is the cause of the biomarkers.
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