Hypothesis\nReversible, chaperone‑rich aggregates act as a temporary sink for damaged proteins, and their conversion into irreversible, toxic deposits is controlled by the acetylation state of aggregate‑associated proteins. Loss of lysine acetylation exposes hydrophobic patches, diminishes chaperone binding, and drives a phase‑separation transition from liquid‑like to solid‑like states. Maintaining acetylation preserves the protective, dynamic nature of aggregates and delays neurodegeneration.\n\n## Mechanistic Basis\n- Acetylation of lysine residues on aggregation‑prone proteins (e.g., tau, α‑synuclein) reduces their net positive charge and weakens intermolecular hydrophobic interactions {Protein aggregation as a protective mechanism}}.\n- This modification creates binding sites for bromodomain‑containing chaperones (e.g., BPTF) that stabilize liquid‑like assemblies and promote disaggregation {Stress granules form via liquid-liquid phase separation}}.\n- In aged cells, declining acetyltransferase activity (e.g., p300/CBP) and rising deacetylase activity (HDAC6, SIRT2) shift the balance toward deacetylation {Protein thiol alterations drive aberrant phase separation}}.\n- Deacetylated aggregates recruit fewer chaperones, exhibit increased β‑sheet content, and undergo an irreversible gel‑to‑solid transition, seeding pathology {TRiC chaperone complex in centenarians}}.\n\n## Testable Predictions\n1. Chemical manipulation – Neuronal overexpression of p300 will increase lysine acetylation on insoluble tau and α‑synuclein, keep aggregates soluble in fractionation assays, and reduce neurodegeneration in aged mouse models {Calorie restriction reduces protein insolubility}}.\n2. Pharmacological inhibition – Treatment with selective HDAC6 inhibitors will mimic the acetylation boost, restore chaperone recruitment to aggregates, and reverse behavioral deficits in tau‑transgenic mice {Hormetic aggregation enhances stress survival}}.\n3. Imaging read‑out – Fluorescence recovery after photobleaching (FRAP) of GFP‑tagged tau will show higher mobile fractions in acetylated conditions, indicating liquid‑like dynamics, whereas deacetylated conditions will display low recovery, indicating solid‑like aggregates.\n4. Biomarker correlation – Human post‑mortem brain tissue from cognitively healthy centenarians will exhibit higher acetylation levels on aggregate‑associated proteins compared with age‑matched Alzheimer’s cases {Cognitively healthy centenarians preserve TRiC}}.\n\n## Implications\nIf acetylation governs the protective‑to‑pathological switch, therapeutic strategies that bolster acetyltransferase activity or inhibit specific deacetylases could preserve the cell’s damage‑containment strategy without globally suppressing aggregation. This reframes anti‑aggregation approaches: rather than eliminating aggregates, we aim to keep them in a reversible, chaperone‑enriched state that serves the proteome’s last attempt at order.
