The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.
A primary pathologic component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.
Dickey
Chad A
CA
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Kamal
Adeela
A
Lundgren
Karen
K
Klosak
Natalia
N
Bailey
Rachel M
RM
Dunmore
Judith
J
Ash
Peter
P
Shoraka
Sareh
S
Zlatkovic
Jelena
J
Eckman
Christopher B
CB
Patterson
Cam
C
Dickson
Dennis W
DW
Nahman
N Stanley
NS
Hutton
Michael
M
Burrows
Francis
F
Petrucelli
Leonard
L
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D010766:Phosphorylation; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016875:tau Proteins; D012694:Serine; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases