HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites.
Neurofibrillary tangles (NFTs) are a characteristic neuropathological feature of Alzheimer's disease (AD), and molecular chaperones appear to be involved in the removal of disease-associated hyperphosphorylated tau, a primary component of NFTs. Here, novel HSP90 inhibitors were used to examine the impact of chaperone elevation on clearance of different tau species in transfected cells using a unique quantitative assay. The HSP90 inhibitors reduced levels of tau phosphorylated at proline-directed Ser/Thr sites (pS202/T205, pS396/S404) and conformationally altered (MC-1) tau species, an epitope that is immeasurable by standard Western blot techniques. The selective clearance of these phospho-tau species and MC-1 tau was mediated via the proteasome, while lysosomal-mediated tau degradation seems to lack specificity for certain tau species, suggesting a more general role in total tau removal. Interestingly, tau phosphorylated at S262/S356 within the tau microtubule binding domain was minimally affected by chaperone induction. Overall, our data show that chaperone induction results in the selective clearance of specific phospho-tau and conformationally altered tau species mediated by the proteasome; however, the apparent stability of pS262/S356 tau may also explain why MARK is able to regulate normal tau function yet still be linked to the initiation of pathogenic tau hyperphosphorylation in AD.
Dickey
Chad A
CA
Mayo Clinic Jacksonville, College of Medicine, Jacksonville, Florida, USA.
Dunmore
Judith
J
Lu
Bingwei
B
Wang
Ji-Wu
JW
Lee
Wing C
WC
Kamal
Adeela
A
Burrows
Francis
F
Eckman
Christopher
C
Hutton
Michael
M
Petrucelli
Leonard
L
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D006224:Cricetinae; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D010769:Phosphothreonine / Q000378:metabolism*; D011392:Proline / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D006360:Heat-Shock Proteins; D016875:tau Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; D011392:Proline