Prion diseases are composed of a group of fatal
neurodegenerative disorders resulting from misfolding of cellular
prion (PrP(C)) into
scrapie prion (PrP(Sc)).
Sirt1, a class III
histone deacetylase, has been reported to protect neuronal cells against PrP (106-126)-induced cell death. To address the potential role of
Sirt1 during
prion infection, the levels and
enzyme activities of
Sirt1 in the brains of
scrapie-infected rodents, including hamsters infected with strain 263K, mice infected with strains 139A and ME7, and in
prion infected SMB-S15 cells, were analyzed. Western blots revealed that endogenous
Sirt1 levels were significantly decreased in all tested
scrapie-infected models. Dynamic assays of brain
Sirt1 levels in 263K-infected hamsters during incubation period showed a time-dependent decrease. The acetylating forms of
Sirt1 target
proteins, P53, PGC-1, and STAT3, markedly increased both in the brains of
scrapie-infected rodents and in SMB-S15 cells, representing decreased
Sirt1 activity. Immunofluorescent assays illustrated that
Sirt1 predominately localized in cytosol of SMB-S15 cells but clearly distributed in nucleus of its normal partner cell line, SMB-PS. Moreover, accompanying with increase of
Sirt1 level and decrease of acetyl-P53 level, treatments with
Sirt1 activators
SRT1720 and
resveratrol in SMB-S15 cells significantly reduced PrP(Sc); at the same time, the cellular distribution of
PrP proteins became normal, and the cell proliferating state was slightly improved. These data indicate that
prion infection notably attenuates the
Sirt1 activity in host cells. Sensitivity of the PrP(Sc) to
Sirt1 activators highlights a potential role of
Sirt1 in
prion therapeutics.