Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in the MAPT gene, encoding tau protein, are linked to frontotemporal lobar degeneration (FTLD).
• These mutations cause neurofibrillary tangles, neurodegeneration, and cognitive decline.
• Pathogenic MAPT mutations can alter tau protein's aggregation propensity.

Purpose of the Study:

• To investigate the in vitro aggregation mechanisms of specific pathogenic tau mutants.
• To determine how missense mutations affect the kinetics of tau fibril formation.

Main Methods:

• Recombinant full-length human tau protein with pathogenic mutations (R5L, G272V, P301L, V337M, R406W) was prepared.
• Fibrillization kinetics were studied using electron microscopy over time and at varying tau concentrations.
• Aggregation kinetic constants for nucleation and extension phases were estimated via direct measurement and mathematical simulation.

Main Results:

• Mutant tau proteins exhibited varying aggregation propensities compared to wild-type tau.
• G272V and P301L mutations accelerated both tau filament nucleation and extension rates.
• R5L and V337M mutations primarily increased the nucleation phase rate.
• The R406W mutation showed no significant difference from wild-type tau in aggregation kinetics.

Conclusions:

• Missense mutations in the MAPT gene can directly influence tau aggregation pathways.
• Different mutations affect distinct stages of tau filament formation, from nucleation to extension.
• Understanding these mutation-specific effects is crucial for FTLD pathogenesis research.