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Hyperacetylation mimetics within the tau filament core inhibits prion-like propagation of misfolded tau. | LitMetric

AI Article Synopsis

  • Acetylation of specific lysine residues in tau protein is associated with neurodegenerative diseases like Alzheimer's and Progressive Supranuclear Palsy, influencing tau's aggregation behavior.
  • Experiments showed that acetylation-mimicking substitutions on key lysine sites reduced tau aggregation initiated by disease-related seeds, suggesting that acetylation can inhibit tau's aggregation process.
  • Additionally, combining acetylation-mimicking substitutions with a phosphorylation-mimicking change revealed specific dependencies on tau seeding from different diseases, with certain modifications leading to spontaneous aggregation, indicating a complex relationship between acetylation, phosphorylation, and tau pathology.

Article Abstract

Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). This has led to the idea that acetylation influences tau aggregation. Using a HEK293 cell-based aggregation assay, we tested whether acetylation-mimicking substitutions (K→Q) on five AD-associated acetyl-modified sites (AcK-311, 353, 369, 370, 375) influenced its propensity to aggregate when exposed to tau seeds derived from two clinically distinctive diseases - AD and PSP. In combination, the presence of 5K→Q sites ablated tau aggregation induced by seeds from both AD and PSP patients, indicating that acetylation within the filament core domain of tau could have an inhibitory effect on seed-mediated aggregation. We had previously identified that a phosphorylation-mimetic on Ser305 (S→E) abrogated tau aggregation by seeds from AD patients, without affecting seeding by PSP patients. Combining the S305→E to the 5K→Q acetyl-modified sites, we found that this tau could now be seeded only by PSP patients, but not by AD patients, confirming Ser305 as a critical determinant of strain-specific tau seeding. On the other hand, acetylation-nullifying substitutions (K→R or K→A) on these same Lys sites did not alter tau seeding abilities compared to the parental tau construct. Notably, the combined acetylation-nullifying Alanine substitutions on these 5 Lys sites resulted in spontaneous self-aggregation, with the filaments resembling amorphous deposits. All together, we demonstrate that cooperative acetyl-occupancy in the tau filament core influences seeded propagation of misfolded tau as well as drives self-aggregation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11042196PMC
http://dx.doi.org/10.1101/2024.04.12.589253DOI Listing

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