Premium
O2‐05–08: Protein O‐Glcnacylation: A novel mechanism involved in Alzheimer's disease
Author(s) -
Gong Cheng-Xin,
Liu Fei,
Liu Ying,
Deng Yanqiu,
Grundke-Iqbal Inge,
Iqbal Khalid
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.347
Subject(s) - neurofilament , phosphorylation , hyperphosphorylation , tau protein , dephosphorylation , microbiology and biotechnology , hippocampus , biology , downregulation and upregulation , chemistry , neurofibrillary tangle , alzheimer's disease , biochemistry , neuroscience , medicine , phosphatase , immunology , senile plaques , immunohistochemistry , disease , gene
vitro aggregation assays employing unmodified recombinant tau isoforms, transmission electron microscopy based detection methods, and a smallmolecule inducer of tau aggregation (Thiazine red) were used to assess the affect of tau structure on aggregation propensity at the level of elementary rate constants. Results: Kinetic analysis revealed that the rate-limiting step in the fibrillization of assembly competent tau conformations was formation of a dimeric nucleus, and that filament elongation proceeded via addition of tau monomers to nascent filament ends. All alternatively spliced segments influenced the rate and/or extent of the reaction. The greatest differences were seen with Exon 10 encoded sequences, which decreased critical concentration ca. 6-fold, and also speeded nucleation rate. The former effect synergized with Exon 2, so that together, Exons 2 and 10 could modulate aggregation propensity by a full order of magnitude. Conclusions: (1) The deduced tau aggregation pathway predicts bottlenecks that must be overcome for neurofibrillary lesions to form in disease. (2) Changes in isoform composition can promote tau fibrillization by directly modulating these reaction bottlenecks. (3) Exon-10, which encodes the fourth microtubule-binding repeat, is the major naturally-occurring modulator of tau aggregation kinetics.