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Preprint WatchMildAugust 26th, 2026

Glycogen Synthase Kinase-3β Regulates Cellular Prion Protein Levels

Beauchemin, K. S.; Schmoker, A. M.; Watts, J. C.; Supattapone, S.

GSK-3 beta regulates cellular prion protein levels through a post-translational mechanism, and two GSK-3 inhibitors, laduviglusib and AZD-1080, reduced cellular prion protein in mouse and human neuronal cell lines, positioning GSK-3 beta as a route to lowering an essential prion disease substrate.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint positions GSK-3 beta as a druggable regulator of cellular prion protein levels, showing that Gsk3b knockdown or knockout and two GSK-3 inhibitors each lowered the protein through a post-translational route. Claidex holds one GSK3B failure, lithium-unc13a-magnet-als-biomarker-failure, in which a genotype-stratified Phase 3 of lithium in amyotrophic lateral sclerosis failed on its biomarker premise rather than on target engagement. That is a weaker warning than an efficacy failure would be, and the flag is graded accordingly. The transferable lesson is about stratification rather than about the target: the prior failure turned on a genotype hypothesis that did not hold, so a GSK-3 beta programme in prion disease should define upfront how it will demonstrate that lowering cellular prion protein in a cell line predicts a patient-level effect.

Abstract excerpt

The normal cellular prion protein (PrPC) is an essential substrate in all forms of prion diseases and a receptor for A{beta} oligomers in Alzheimers disease. However, it is not fully understood how cells regulate PrPC levels. Recently, we identified glycogen synthase kinase-3{beta} (GSK-3{beta}) as a potential regulator of PrPC levels in a whole genome knockout screen. Here, we show that both cell surface and total PrPC levels can be reduced either by siRNA-mediated Gsk3b (but not Gsk3a) knockdown or by CRISPR-mediated Gs3b knockout. Whole cell mass spectrometric analysis showed that PrPC was the 60th most significantly reduced protein (out of 7227 total proteins detected) in Gsk3b knockout cells, compared to wild-type cells. Two different GSK-3 inhibitors, laduviglusib (CHIR-99021) and AZD-1080, reduced PrPC levels in mouse CAD5 and human BE(2)-C cells, both in undifferentiated and differentiated states. PrPC levels were similarly reduced by cycloheximide treatment in both Gsk3b knockout and WT cells, indicating that GSK-3{beta} regulates PrPC levels through a post-translational mechanism. Finally, treatment with either laduviglusib or AZD-1080 reduced PrPSc levels in CAD5 cells infected with three different rodent prion strains. Overall, the results reveal that GSK-3{beta} activity controls PrPC levels in living cells, revealing a novel regulatory mechanism and promising therapeutic target.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.