Title : Molecular pathogenesis of Tau disorders
Abstract:
In the recently proposed taxonomy, tauopathies are classified according to isoform composition and lamination pattern of the protofilament core region (Shi Y et al Nature 2021, 598:359-363). Here we expand on this classification to retrace the initiating events of pathogenic fibrillization of tau. Our approach is to exploit backbone-based model of nucleated polymerization of tau and amyloid β along with the available experimental data (Cieplak AS Front Neurosci 2019, 13:488). In this model, the core region of tau protofilaments is determined by the stereochemical and spatiotemporal dimensions of primary nucleation. The initial steps involve coupled binding and folding of ‘unveiled’ MTB domains to form antiparallel dimers of 2-fold symmetry, assembly of the dimers into hexamers which fold into metamorphic paranuclei, and a shift of metamorphic equilibrium to form cross-β spine nuclei. Coordinates of this process are defined based on the etiology of tauopathies and the plots of the folding potential FPi (Cieplak AS PLoS ONE 2017, 12:0180905) which identify (i) antiparallel dimers consistent with the morphology of the in vivo and in vitro fibrillization, and (ii) protein cofactors that may facilitate nucleation in vivo. The results suggest that the conditions which trigger two key steps of pathogenic aggregation of tau, the ‘unveiling’ of MTB domains and metamorphosis of paranuclei, are specific to each brain area where the pathology commences. Elucidation of these conditions may point to disorderspecific targets for drug development.
