Site-Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

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

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The consistent observation of phosphorylated tau in the pathology of Alzheimer's disease has contributed to the emergence of a model where hyperphosphorylation triggers both tau disassociation from microtubules and its subsequent aggregation. Herein, we applied a total chemical synthetic approach to site-specifically phosphorylate the microtubule binding repeat domain of tau (K18) at single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues. We show that hyperphosphorylation of K18 inhibits 1) its aggregation in vitro, 2) its seeding activity in cells, 3) its binding to microtubules, and 4) its ability to promote microtubule polymerization. The inhibition increased with increasing the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. Our results argue against the hyperphosphorylation hypothesis and underscore the importance of revisiting the role of site-specific hyperphosphorylation in regulating tau functions in health and disease.

Original languageEnglish (US)
Pages (from-to)4059-4067
Number of pages9
JournalAngewandte Chemie - International Edition
Volume59
Issue number10
DOIs
StatePublished - Mar 2 2020

Keywords

  • aggregation
  • hyperphosphorylation
  • native state stabilization
  • protein modifications
  • tau protein

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Fingerprint Dive into the research topics of 'Site-Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding'. Together they form a unique fingerprint.

  • Cite this