Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease.
Alzheimer's disease is a tauopathy which involves the deposition of microtubule-associated tau proteins into neurofibrillary tangles. Post-translational modifications, in particular site-specific phosphorylations, affect the conformation of tau protein which is an intrinsically disordered protein. These structural changes significantly increase the affinity of tau protein for certain molecular chaperones. Hsp90 is a major cellular chaperone which assembles large complexes with a variety of co-chaperones. The main function of Hsp90 complexes is to maintain protein quality control and assist in protein degradation via proteasomal and autophagic-lysosomal pathways. Tau protein is a client protein for these Hsp90 complexes. If the tau protein is in an abnormal or modified form, then it can trigger the recruitment of CHIP protein, a co-chaperone with E3 activity, to the complex which induces the ubiquitination of tau protein and activates its downstream degradation processes. Large immunophilins, FKBP51 and FKBP52 are also co-chaperones of Hsp90-tau complexes. These proteins contain peptidylprolyl cis/trans isomerase activity which catalyzes phosphorylation-dependent rotation in pSer/Thr-Pro peptide bond. The proline switch in the tau conformation triggers dephosphorylation of Ser/Thr residues phosphorylated, e.g. by two well-known tau kinases Cdk5 and GSK-3β. Binding of PP5 protein phosphatase to Hsp90 complex, can also dephosphorylate tau protein. Subsequently, dephosphorylated tau protein can be shuttled back to the microtubules. It seems that high-affinity binding of abnormal tau to Hsp90 complexes may have some counteracting effects on the aggregation process, since Hsp90 inhibitors can ameliorate the aggregation process in several neurodegenerative diseases. We will review the role of Hsp90 chaperone network in the regulation of tau biology and pathology in Alzheimer's disease.
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uef.fi
Antero
A
Salminen
Johanna
J
Ojala
Kai
K
Kaarniranta
Mikko
M
Hiltunen
Hilkka
H
Soininen
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex