SIRT1 protects against α-synuclein aggregation by activating molecular chaperones.
α-Synuclein is a key molecule in the pathogenesis of synucleinopathy including dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Sirtuins are NAD(+)-dependent protein deacetylases that are highly conserved and counter aging in lower organisms. We show that the life span of a mouse model with A53T α-synuclein mutation is increased by overexpressing SIRT1 and decreased by knocking out SIRT1 in brain. Furthermore, α-synuclein aggregates are reduced in the brains of mice with SIRT1 overexpression and increased by SIRT1 deletion. We show that SIRT1 deacetylates HSF1 (heat shock factor 1) and increases HSP70 RNA and protein levels, but only in the brains of mice with A53T and SIRT1 expression. Thus, SIRT1 responds to α-synuclein aggregation-induced stress by activating molecular chaperones to protect against disease.
Paul F. Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Gizem
G
Donmez
Anirudh
A
Arun
Chee-Yeun
CY
Chung
Pamela J
PJ
McLean
Susan
S
Lindquist
Leonard
L
Guarente
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000502:physiology*; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics*; D013312:Stress, Physiological / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D018832:Molecular Chaperones; C497605:Snca protein, mouse; D051844:alpha-Synuclein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1