Hsp90 activator Aha1 drives production of pathological tau aggregates

Abstract

The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer's disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood-brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

Dynamic Aha1 co‐chaperone binding to human Hsp90

“…E67K-Aha1 is unable to stimulate the ATPase activity of Hsp90 due to impaired binding 12 and failure to induce Hsp90 closed conformations and is ineffective in promoting Hsp90-dependent maturation 12 or aggregation of clients. 23 Consistent with these data, binding of E67K-Aha1 to human Hsp90 was weaker and did not result in new Hsp90 cross-peaks ( Figure S5a,b). Besides the mentioned need of both Hsp90M domains for a stable interaction with Aha1-N, this impaired binding can be rationalized based on the atomic structure of the yeast Hsp90M/ Aha1-N-complex.…”

“…To confirm the importance of the interaction of the N‐terminal domain of Aha1 with the middle domains of Hsp90, as seen in the complex structure of the two isolated domains and in our NMR data (Figure c), we characterized the binding of the mutant protein E67K‐Aha1 to Hsp90. E67K‐Aha1 is unable to stimulate the ATPase activity of Hsp90 due to impaired binding and failure to induce Hsp90 closed conformations and is ineffective in promoting Hsp90‐dependent maturation or aggregation of clients . Consistent with these data, binding of E67K‐Aha1 to human Hsp90 was weaker and did not result in new Hsp90 cross‐peaks (Figure S5a,b).…”

The molecular mechanism of Hsp90-induced oligomerization of Tau

“…It is important to note that the sketch is not an accurate model of Tau structure, but an attempt to unite the most relevant results of this study in one possible Tau molecule representing the whole conformational ensemble. The N-terminal domain forms long-range interactions with the aggregation-prone domain, in line with previous findings (22)(23)(24). The flexible N-terminus may, therefore, preclude aberrant Tau/Tau interactions, resulting in the high solubility of the full-length protein.…”

“…The molecular chaperone Hsp90 (17,18) initiates proteasomal degradation (19)(20)(21) and induces oligomerization of Tau (22)(23)(24). Tau-RD is part of the Hsp90/Tau interaction interface (25).…”

Proteomic interrogation of HSP90 and insights for medical research

“…Recently, Shelton et al [62] specifically studied the interaction of HSP90α and P301L tau with Aha1, p23, CDC37, FKBP4, and FKPB5 in the context of tau fibril formation. Their results show that only Aha1 enhanced the fibril formation in vitro , and that it required ATP.…”