Biochemical and biophysical features of disease-associated tau mutants V363A and V363I

The comprehension of pathogenetic mechanisms in tauopathy-associated neurodegenerative diseases can be
improved by the knowledge of the biochemical and biophysical features of mutated tau proteins. Here, we used
the full-length, wild-type tau, the V363A and V363I mutated species, associated with pathology, and the P301L
mutated tau as a benchmark. Using several techniques, including small-angle X-ray scattering, atomic force
microscopy, thioflavin T binding, and electrophoretic separation, we compared their course from intrinsically
disordered monomers in solution to early-stage recruitment in complexes and then aggregates of increasing size
over long periods up to the asymptotic aggregative behavior of full-length tau proteins. We showed that diversity
in the kinetics of recruitment and aggregate structure occurs from the beginning and spreads all over their
pathway to very large objects. The different extents of conformational changes and types of molecular assemblies
among the proteins were also reflected in their in vitro toxicity; this variation could correlate with physiopathology
in humans, considering that the P301L mutation is more aggressive than V363A, especially V363I. This
study identified the presence of aggregation intermediates and corroborated the oligomeric hypothesis of
tauopathies.