Hsp70 Alters Tau Function
and Aggregation in an Isoform Specific Manner
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Abstract
Tauopathies are characterized by abnormal aggregation
of the microtubule associated protein tau. This aggregation is thought
to occur when tau undergoes shifts from its native conformation to
one that exposes hydrophobic areas on separate monomers, allowing
contact and subsequent association into oligomers and filaments. Molecular
chaperones normally function by binding to exposed hydrophobic stretches
on proteins and assisting in their refolding. Chaperones of the heat
shock protein 70 (Hsp70) family have been implicated in the prevention
of abnormal tau aggregation in adult neurons. Tau exists as six alternatively
spliced isoforms, and all six isoforms appear capable of forming the
pathological aggregates seen in Alzheimer’s disease. Because
tau isoforms differ in primary sequence, we sought to determine whether
Hsp70 would differentially affect the aggregation and microtubule
assembly characteristics of the various tau isoforms. We found that
Hsp70 inhibits tau aggregation directly and not through inducer-mediated
effects. We also determined that Hsp70 inhibits the aggregation of
each individual tau isoform and was more effective at inhibiting the
three repeat isoforms. Finally, all tau isoforms robustly induced
microtubule formation while in the presence of Hsp70. The results
presented herein indicate that Hsp70 affects tau isoform dysfunction
while having very little impact on the normal function of tau to mediate
microtubule assembly. This indicates that targeting Hsp70 to tau may
provide a therapeutic approach for the treatment of tauopathies that
avoids disruption of normal tau function