The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson's Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia

被引：98

作者：

Chen, Xiqun ^{[1
]}

Wales, Pauline ^{[2
]}

Quinti, Luisa ^{[1
]}

Zuo, Fuxing ^{[1
]}

Moniot, Sebastien ^{[3
]}

Herisson, Fanny ^{[1
]}

Rauf, Nazifa Abdul ^{[1
]}

Wang, Hua ^{[4
]}

Silverman, Richard B. ^{[4
]}

Ayata, Cenk ^{[1
]}

Maxwell, Michelle M. ^{[1
]}

Steegborn, Clemens ^{[3
]}

Schwarzschild, Michael A. ^{[1
]}

Outeiro, Tiago F. ^{[2
]}

Kazantsev, Aleksey G. ^{[1
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02129 USA

[2] Univ Med Ctr Goettingen, Ctr Nanoscale Microscopy & Mol Physiol Brain, Dept NeuroDegenerat & Restorat Res, D-37073 Gottingen, Germany

[3] Univ Bayreuth, Dept Biochem, D-95447 Bayreuth, Germany

[4] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chem Life Proc Inst, Dept Chem,Dept Mol Biosci, Evanston, IL 60208 USA

来源：

PLOS ONE | 2015年 / 10卷 / 01期

关键词：

MOUSE MODEL; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; SIRT2; DEACETYLASE; PROTEIN; POLYMORPHISM; GENERATION; RS10410544; DESIGN;

D O I：

10.1371/journal.pone.0116919

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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