Pseudophosphorylation of tau protein directly modulates its aggregation kinetics.
Hyperphosphorylation of tau protein is associated with neurofibrillary lesion formation in Alzheimer's disease and other tauopathic neurodegenerative diseases. It fosters lesion formation by increasing the concentration of free tau available for aggregation and by directly modulating the tau aggregation reaction. To clarify how negative charge incorporation into tau directly affects aggregation behavior, the fibrillization of pseudophosphorylation mutant T212E prepared in a full-length four-repeat tau background was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods. Kinetic constants for nucleation and extension phases of aggregation were then estimated by direct measurement and mathematical simulation. Kinetic analysis revealed that pseudophosphorylation increased tau aggregation rate by increasing the rate of filament nucleation. In addition, it increased aggregation propensity by stabilizing mature filaments against disaggregation. The data suggest that incorporation of negative charge into the T212 site can directly promote tau filament formation at multiple steps in the aggregation pathway.
Chang
Edward
E
Center of Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Kim
Sohee
S
Schafer
Kelsey N
KN
Kuret
Jeff
J
D000544:Alzheimer Disease / Q000378:metabolism; D019943:Amino Acid Substitution; D001665:Binding Sites; D004563:Electrochemistry; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
C054369:MAPT protein, human; D011994:Recombinant Proteins; D016875:tau Proteins