Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation
Abstract Alzheimer’s disease is the leading cause of dementia and a defining hallmark is the progressive brain deposition of tau aggregates. The insidious accumulation of brain tau inclusions is also involved in a group of neurodegenerative diseases termed frontotemporal dementias. In all of these d...
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| Autores principales: | , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/5e68b23b90da44048588b671bf648a63 |
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| Sumario: | Abstract Alzheimer’s disease is the leading cause of dementia and a defining hallmark is the progressive brain deposition of tau aggregates. The insidious accumulation of brain tau inclusions is also involved in a group of neurodegenerative diseases termed frontotemporal dementias. In all of these disorders, tau aggregates are enriched in post-translational modifications including acetylation, which has recently been identified at multiple sites. While most evidence suggest that tau acetylation is detrimental and promotes tau aggregation, a few studies support that tau acetylation within the KXGS motif can be protective and inhibit tau aggregation. To model site-specific acetylation at K259, K290, K321, and K353, acetylmimetics were created by mutating lysine to glutamine residues, which approximates size and charge of acetylation. HEK293T cells were transfected to express wild type tau, tau pathogenic mutations (P301L and P301L/S320F) or tau acetylmimetics and assessed by cell-based assays for microtubule binding and tau aggregation. Acetylmimetics within the KXGS motif (K259Q, K290Q, K321Q, K353Q) leads to significant decreased tau–microtubule interactions. Acetylmimetics K321Q and K353Q within the context of the pathogenic P301L tau mutation strongly inhibited prion-like seeded aggregation. This protective effect was confirmed to decrease intrinsic aggregation of P301L/S320F tau double mutation. Surprisingly, K321Q and K353Q acetylmimetics altered the conformational structure of P301L/S320F tau to extensively impair Thioflavin S binding. Site-specific acetylation of tau at K321 and K353 could represent a natural protective mechanism against tau aggregation and could be a potential therapeutic target. |
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