In this week's early online edition of PNAS, researchers report that chaperones may play a vital role in regulating protein aggregation in Alzheimer's disease (AD).
Led by Huaxi Xu, Rockefeller University, New York, an international collaboration of scientists from the United States, Japan, and Germany, examined heat shock protein (Hsp70/90) levels in transgenic mice expressing the mutant form of the human protein tau that is associated with frontotemporal dementia and specific forms of Parkinson's disease. Tau is the major component of neurofibrillary tangles, a hallmark of AD. First author Fei Dou et al. found an inverse relationship between tau aggregation and chaperone levels-transgenic mice harboring tau aggregates had much lower levels of Hsp90 than control mice. Furthermore, the authors found that a small number of neurons in the hippocampus that are devoid of aggregating tau have significantly higher levels of this chaperone. Dou at al. also reveal the same link between heat shock proteins and tau aggregates in post-mortem samples from a single human AD brain.
The authors examined the cause-and-effect relationship between chaperones and tau aggregation by inducing expression of Hsp70 and Hsp90 in cells expressing various forms of human tau. Four- and 10-fold higher levels of Hsp90 and Hsp70, respectively, led to an almost 80 percent reduction in tau aggregation. This effect was more significant in a tau-mutant background, perhaps not surprisingly, as the mutants have a greater propensity to aggregate.
So what happens to tau that is solubilized by heat shock proteins? The data of Dou et al. suggest that it finds a home in the microtubules that crisscross the cytosol. When the authors silenced expression of either Hsp70 or Hsp90 with small interfering RNAs, the levels of microtubule-bound tau fell by almost 75 percent, while induction of Hsp expression increased this association by approximately twofold.
The data strongly suggest that the inherent ability of chaperones to solubilize misfolded proteins may play a significant role in the pathology of Alzheimer's disease, as is the thought to be the case with some other neurodegenerative diseases, such as Parkinson's and Huntington's.—Tom Fagan
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- Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H. Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):721-6. PubMed.