Heat shock proteins protect against stress-related phosphorylation of tau in neuronal PC12 cells that have acquired thermotolerance.
A68, or PHF-tau, is an abnormally phosphorylated form of the microtubule-associated protein tau, which is a primary protein constituent of paired helical filaments (PHFs) and, ultimately, of Alzheimer's disease-associated neurofibrillary tangles (NFTs). Previously, we have shown that in heat-shocked neuronal PC12 cells, tau is hyperphosphorylated and transformed to an A68-like state as determined by immunologic and biochemical criteria. In the present study, we investigated the role of heat shock protein of 72 kDa (hsp72) in the protection of tau against hyperphosphorylation during heat shock. Neuronal PC12 cells were exposed either directly to a heat shock (45 degrees C for 30 min) or to a conditioning heat stress (43 degrees C for 90 min followed by a 4 hr recovery at 37 degrees C) followed by the heat shock. Hsp72 was maximally induced immediately after heat shock in conditioned (acquired thermotolerant, ATT) cells, while unconditioned (nonacquired thermotolerant, non-ATT) cells required 9 hr of recovery to exhibit maximal hsp72 induction. The differential time course of hsp72 induction during recovery of ATT and non-ATT cells correlated with the presence of normal tau. Immediately after the heat shock, when hsps were maximally induced, ATT cells exhibited the normal form of tau. With longer recovery times, the levels of hsp72 were reduced and tau was hyperphosphorylated. A similar correlation was observed in non-ATT cells. In the presence of L-azetidyl 2-carboxylic acid, ATT cells synthesized nonfunctional hsp72, as exhibited by the inability of the cells to recover from the effects of heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)
Kirby
B A
BA
Molecular Geriatrics Corporation, Lake Bluff, Illinois 60044.
Merril
C R
CR
Ghanbari
H
H
Wallace
W C
WC
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology*; D006358:Hot Temperature; D009416:Nerve Regeneration; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013312:Stress, Physiological / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D001384:Azetidines; D006360:Heat-Shock Proteins; D016875:tau Proteins; C089382:azetidyl-2-carboxylic acid