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.
Highlights
Alzheimer’s disease is the leading cause of dementia and a defining hallmark is the progressive brain deposition of tau aggregates
We wanted to systematically assess the impact of acetylation sites (K259, K290, K321, and K353) within the KXGS motifs that are located within the MT-binding region (Fig. 1)
MT binding of tau acetylmimetics compared to wild type (WT) human tau was assessed using a cell-based MT cosedimentation assay, which has been previously used to investigate the effects of tau pathogenic mutations and phosphomimetics[18,19]
Summary
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 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. Brain pathological tau inclusions are one of the major defining hallmark in Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other neurodegenerative disorders called tauopathies[1]. While most evidence suggests tau acetylation contributes to disease, several studies provided evidence that specific acetylation sites within the KXGS motifs (K259, K290, K321, K353) could be p rotective[15,16]. Acetylation of KXGS motifs can be mediated by p300 acetyltransferase[5,16] and deacetylated by histone deacetylase 6 (HDAC6)[15]
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