Structural insights into Alzheimer filament assembly pathways based on site-directed mutagenesis and S-glutathionylation of three-repeat neuronal Tau protein

Luca Dinoto, Michael Deture, Daniel L. Purich

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.

Original languageEnglish (US)
Pages (from-to)156-163
Number of pages8
JournalMicroscopy Research and Technique
Volume67
Issue number3-4
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

mutagenesis
tau Proteins
Mutagenesis
site-directed mutagenesis
Site-Directed Mutagenesis
Microtubules
Polymerization
polymerization
Dimers
microtubules
filaments
assembly
proteins
Proteins
Neurofibrillary Tangles
Aptitude
Alzheimer disease
thiols
sulfides
Sulfhydryl Compounds

Keywords

  • Aberrant protein polymerization
  • Cytoskeletal protein
  • Glutathione
  • MAP2
  • Microtubule-associated proteins
  • Oxidative stress

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Anatomy
  • Instrumentation

Cite this

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abstract = "Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.",
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AB - Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.

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