| First Author | Ajit D | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 45 | Pages | 16698-16711 |
| PubMed ID | 31543505 | Mgi Jnum | J:283076 |
| Mgi Id | MGI:6383618 | Doi | 10.1074/jbc.RA119.009674 |
| Citation | Ajit D, et al. (2019) A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation. J Biol Chem 294(45):16698-16711 |
| abstractText | Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches. |
