Site-specific hyperphosphorylation of tau inhibits its fibrillization in vitro, blocks its seeding capacity in cells, and disrupts its microtubule binding; Implications for the native state stabilization of tau

Mahmood Haj-Yahya, Pushparathinam Gopinath, Kolla Rajasekhar, Hilda Mirbaha, Marc I. Diamond, Hilal A. Lashuel

Research output: Contribution to journalArticlepeer-review

Abstract

The consistent observation of aggregated phosopho-tau in the pathology of Alzheimer’s disease and other tauopathies has contributed to the emergence of a model where hyperphosphorylation of tau causes its disassociation from microtubules and subsequent pathological polymerization. However, the large number of possible phosphorylation sites in tau and lack of robust methods that enable the preparation of homogeneously phosphorylated tau species have made it difficult to validate this model. Herein, we applied a total chemical synthetic approach to site-specifically phosphorylate single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues within the microtubule binding repeat domain (MTBD) of tau and show that hyperphosphorylation within the microtubule MTBD inhibits K18 tau 1) aggregation in vitro; 2) its seeding activity in cells, and 3) its ability to promote microtubule polymerization. The inhibition increased with the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. On the basis of these findings, we propose that targeting the kinases that regulate phosphorylation at these sites could provide a viable strategy to stabilize the native state of tau and inhibit its aggregation. Taken together, our results argue against the pathogenic hyperphosphorylation hypothesis and underscore the critical importance of revisiting the role of site-specific hyperphosphorylation of tau in regulating its function in health and disease. biorxiv;772046v1/UFIG1F1ufig1Table of content

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Sep 18 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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