Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease.
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.
Steele
Andrew D
AD
Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Hutter
Gregor
G
Jackson
Walker S
WS
Heppner
Frank L
FL
Borkowski
Andrew W
AW
King
Oliver D
OD
Raymond
Gregory J
GJ
Aguzzi
Adriano
A
Lindquist
Susan
S