Inert and seed-competent tau monomers suggest structural origins of aggregation

Abstract

Tauopathies feature progressive accumulation of tau amyloids. Pathology may begin when these amplify from a protein template, or seed, whose structure is unknown. We have purified and characterized distinct forms of tau monomer—inert (Mi) and seed-competent (Ms). Recombinant Ms triggered intracellular tau aggregation, induced tau fibrillization in vitro, and self-assembled. Ms from Alzheimer’s disease also seeded aggregation and self-assembled in vitro to form seed-competent multimers. We used crosslinking with mass spectrometry to probe structural differences in Mi vs. Ms. Crosslinks informed models of local peptide structure within the repeat domain which suggest relative inaccessibility of residues that drive aggregation (VQIINK/VQIVYK) in Mi, and exposure in Ms. Limited proteolysis supported this idea. Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form.

Mechanisms of secretion and spreading of pathological tau protein

“…However, the pathway of tau fibrillization may not be as straightforward as it seems. A recent study demonstrated that different stable monomeric forms of tau with different seeding abilities coexist, implying that different seeds could originate from their aggregation [40]. This study also raises the possibility that tau, despite being natively unfolded, may physiologically exist in relatively stable conformations that affect its propensity to adopt a pathological form.…”

“…Moreover, the morphological features of the original tau seeds can be faithfully recapitulated in the newly formed tau aggregates [74,135]. Moreover, specific monomeric conformers have been shown to have different intrinsic abilities to become pathogenic, and they can give rise to a limited amount of strains, suggesting that the misfolding is closely related to the structure of the original seed [40,41].…”

“…Image was prepared based on a cryo-EM structure (PDB: 5O3L) electron microscopy (cryo-EM) have provided insight into conformational states of tau, in soluble physiological state, bound to microtubules or in the form of pathological aggregated states. It was also recently suggested that under physiological conditions tau monomers may adopt stable yet diverse conformations, opening a new perspective for understanding the plasticity of tau structure in physiology and in pathology [40,41].…”

“…This partially explains the higher propensity of 4R isoforms to aggregate compared to 3R isoforms. Local structural changes of the MTBDs via exposure of the VQIVYK/VQIINK motifs may determine the conversion of an inert tau monomer into a pathologically aggregated form [40]. Tau dimerization, the first step in tau oligomerization, can occur through any combination of these two motifs, which form the nucleation center where further tau dimers and tau monomers can be recruited to eventually constitute oligomers.…”

Cofactors are essential constituents of stable and seeding-active tau fibrils

“…It was recently proposed that after aggregation, tau, even in its monomeric form, maintains aggregate-templated conformations that provide high seeding capacities (24). According to this hypothesis, the aggregation propensity of the tau monomers released from the digested fibrils should be much higher than that of fresh tau monomers, as the released monomers would populate fibrillation-prone conformations with increased numbers of nucleation sites in the sample.…”