How does the reversibility of tau acetylation reconcile with stable prion-like propagation models?

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Description

The debate highlighted that acetyltransferases and deacetylases dynamically regulate K280 acetylation within hours, yet prion models require stable templating. This fundamental contradiction needs mechanistic resolution for therapeutic targeting.

Source: Debate session sess_SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd_20260412-091505 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd)

Resolution criteria

Resolved when tau K280 acetylation dynamics are measured in seeded propagation models and reconciled with aggregate stability. Required evidence: time-resolved acetyl-proteomics or site-specific tau immunoassays after manipulating p300/CBP and HDAC6/SIRT pathways, paired with seeding assays, cryo-EM or conformation-specific aggregate profiling, and cell-to-cell propagation readouts. Closure requires showing whether transient acetylation creates a stable seed-competent tau conformer, is continuously regenerated during propagation, or is not causally required.

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