The Effect of Chaperones on Tau Pathogenic Mutants

The abnormal aggregation of the microtubule-associated protein tau is related to over 20 neurodegenerative conditions, including Alzheimer`s and Pick’s disease. While the tau aggregation trigger is not well understood, it is known to be driven by local structural changes to the microtubule-binding repeats (MTBRs). Such changes trigger the conversion of tau from an intrinsically disordered protein to stable, disease-associated, cross-β amyloids.
In the cell, proteins called chaperones engage with tau during these pathogenic events, counteracting its aggregation and targeting the misfolded species for degradation. Chaperones prevent tau aggregation usually by binding directly to the hydrophobic MTBRs, thus preventing their misfolding and self-association.
Over 50 pathogenic mutations in tau were identified, usually associated with early onset of the disease. Most mutations are located in the MTBRs and are thought to induce conformational change in this region, leading to enhanced tau aggregation. Furthermore, it was hypothesized that these mutants interfere with the chaperone binding sites, allowing these tau variants to evade the cellular chaperone network.
To test this, we used NMR spectroscopy and biochemical methods to characterize the effect of tau pathological mutations on its conformation and interaction with chaperones. Using three chaperone systems, each affecting different stages of aggregation, we show that indeed most chaperone interactions are reduced by the disease-associated mutations.
However, we identified a specific set of chaperones able to efficiently bind and prevent the aggregation of tau mutants. Further mechanistic understanding of this chaperone system, could provide new avenues for treating tau related and aggregation induced diseases.