TY - JOUR
T1 - The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia
AU - Chen, Xiqun
AU - Wales, Pauline
AU - Quinti, Luisa
AU - Zuo, Fuxing
AU - Moniot, Sébastien
AU - Herisson, Fanny
AU - Rauf, Nazifa Abdul
AU - Wang, Hua
AU - Silverman, Richard B.
AU - Ayata, Cenk
AU - Maxwell, Michelle M.
AU - Steegborn, Clemens
AU - Schwarzschild, Michael A.
AU - Outeiro, Tiago F.
AU - Kazantsev, Aleksey G.
N1 - Publisher Copyright:
© 2015 Chen et al.
PY - 2015/1/21
Y1 - 2015/1/21
N2 - Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson's disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson's disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson's disease, and previously in Huntington's disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.
AB - Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson's disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson's disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson's disease, and previously in Huntington's disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.
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U2 - 10.1371/journal.pone.0116919
DO - 10.1371/journal.pone.0116919
M3 - Article
AN - SCOPUS:84921747158
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 1
M1 - e0116919
ER -