Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 36, Pages 13626-13631Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806319105
Keywords
neurodegeneration; HSF1; transmissible spongiform encephalopathy; PrP; protein misfolding
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Funding
- U.S. Dept of Defense [DAMD17-00-1-0296]
- Howard Hughes Medical Institute
- Ellison Medical Research Foundation
- National Institutes of Health-National In stitute of Allergy and Infectious Diseases
- Journal of Cell Science Travel Fellowship
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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 KC) mice had a dramatically shortened lifespan, succumbing to disease approximate to 20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KC) 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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