Steele, Andrew D. and Hutter, Gregor and Jackson, Walter S. and Heppner, Frank L. and Borkowski, Andrew W. and King, Oliver D. and Raymond, Gregory J. and Aguzzi, Adriano and Lindquist, Susan (2008) Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease. Proceedings of the National Academy of Sciences of the United States of America, 105 (36). pp. 13626-13631. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:STEpnas08b
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Prion diseases are fatal, transmissible, neurodegenerative diseases caused by the misfolding of the prion protein (PrP). At present, the molecular pathways underlying prion-mediated neurotoxicity are largely unknown. We hypothesized that the transcriptional regulator of the stress response, heat shock factor 1 (HSF1), would play an important role in prion disease. Uninoculated HSF1 knockout (KO) mice used in our study do not show signs of neurodegeneration as assessed by survival, motor performance, or histopathology. When inoculated with Rocky Mountain Laboratory (RML) prions HSF1 KO mice had a dramatically shortened lifespan, succumbing to disease ≈20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KO and control mice. The accumulation of proteinase K (PK)-resistant PrP also occurred with similar kinetics and prion infectivity accrued at an equal or slower rate. Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease.
|Additional Information:||© 2008 by The National Academy of Sciences of the USA. Communicated by Harvey F. Lodish, Whitehead Institute for Biomedical Research, Cambridge, MA, July 1, 2008 (received for review April 24, 2008). Published online before print August 29, 2008, doi: 10.1073/pnas.0806319105. We thank Artur Topolszki, Melissa Topolszki, Petra Schwarz, and Marianne Konig for expert technical assistance; Karen Allendoerfer for critical comments on the manuscript; and Elisabeth Christians and Ivor Benjamin (University of Utah) for providing the HSF1 knockout mice. This work was supported by U.S. Dept of Defense Grant DAMD17-00-1-0296, the Howard Hughes Medical Institute, the Ellison Medical Research Foundation, the Intramural Research Program at the National Institutes of Health–National Institute of Allergy and Infectious Diseases, and the Journal of Cell Science Travel Fellowship. Author contributions: A.D.S., W.S.J., A.A., and S.L. designed research; A.D.S., G.H., W.S.J., F.L.H., and A.W.B. performed research; G.J.R. contributed new reagents/analytic tools; A.D.S., G.H., W.S.J., F.L.H., O.D.K., G.J.R., A.A., and S.L. analyzed data; and A.D.S. and S.L. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0806319105/DCSupplemental.|
|Subject Keywords:||neurodegeneration; HSF1; transmissible spongiform encephalopathy; PrP; protein misfolding|
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|Deposited On:||09 Sep 2008 02:04|
|Last Modified:||26 Dec 2012 10:16|
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