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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-4215

Steele, A D; Hutter, G; Jackson, W S; Heppner, F L; Borkowski, A W; King, O D; Raymond, G J; Aguzzi, A; Lindquist, S (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 (PNAS), 105(36):13626-13631.

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Abstract

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 approximately 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.

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37 citations in Web of Science®
41 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:9 September 2008
Deposited On:07 Nov 2008 15:53
Last Modified:27 Nov 2013 23:23
Publisher:National Academy of Sciences
ISSN:0027-8424
Additional Information:Copyright: National Academy of Sciences USA
Publisher DOI:10.1073/pnas.0806319105
PubMed ID:18757733

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