Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O'Leary JC, Fontaine SN, Breydo L, Zhang B, Li P, Wang L, Cotman C, Paulson HL, Muschol M, Uversky VN, Klengel T, Binder EB, Kayed R, Golde TE, Berchtold N, Dickey CA. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest. 2013 Oct 1;123(10):4158-69. PubMed.
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Weill Cornell Medical College
The development of tau pathology likely undergoes the following process: tau protein accumulation, oligomerization, fibril and tangle formation. It is essential to identify the toxic species of tau and the factors regulating the formation of these toxic species. Tau protein is intrinsically unstable, rendering it a good substrate for the molecular chaperone Hsp90. Earlier studies from Dr. Dickey's and our group revealed that inhibiting Hsp90 disrupts the interaction between Hsp90 complex and tau, and induces tau degradation both in vitro and in vivo, suggesting a role of Hsp90 in maintaining tau pathology in AD. However it was unclear how Hsp90 complex achieved this. We speculated that, with assistance from different co-chaperones, Hsp90 actively participates in different stages of tau aggregation.
This study from Dr. Dickey’s group demonstrates an essential role of FKBP51, a cochaperone of Hsp90, in tau aggregation during AD. By coordinating with the Hsp90 machinery, FKBP51 alters tau structure, prevents tau degradation, and promotes formation of tau oligomers. Although it remains controversial whether tangle formation is beneficial or toxic, increasingly, studies reveal that oligomeric tau species significantly contribute to toxicity. It is now necessary to identify the specific toxic oligomer(s) using more advanced biochemical or cell biology approaches in order to confirm and further dissect the role of Hsp90 machinery in facilitating toxicity.
Another interesting open question is whether the Hsp90 machinery contributes to tau spreading in brain. These efforts will eventually help the development of AD-related therapeutic tools that inhibit Hsp90 activity or reduc the levels of its cochaperones like FKBP51.
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