The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia

Xiqun Chen, Pauline Wales, Luisa Quinti, Fuxing Zuo, Sébastien Moniot, Fanny Herisson, Nazifa Abdul Rauf, Hua Wang, Richard B. Silverman, Cenk Ayata, Michelle M. Maxwell, Clemens Steegborn, Michael A. Schwarzschild, Tiago F. Outeiro, Aleksey G. Kazantsev

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere0116919
JournalPLoS One
Volume10
Issue number1
DOIs
StatePublished - Jan 21 2015
Externally publishedYes

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Sirtuin 2
Parkinson disease
Amyotrophic Lateral Sclerosis
ischemia
Brain Ischemia
Parkinson Disease
Dopaminergic Neurons
brain
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
alpha-Synuclein
Huntington Disease
Brain
neurodegenerative diseases
dopamine
Neurodegenerative Diseases
protective effect
Neurodegenerative diseases
neurons
animal models
toxicity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia. / Chen, Xiqun; Wales, Pauline; Quinti, Luisa; Zuo, Fuxing; Moniot, Sébastien; Herisson, Fanny; Rauf, Nazifa Abdul; Wang, Hua; Silverman, Richard B.; Ayata, Cenk; Maxwell, Michelle M.; Steegborn, Clemens; Schwarzschild, Michael A.; Outeiro, Tiago F.; Kazantsev, Aleksey G.

In: PLoS One, Vol. 10, No. 1, e0116919, 21.01.2015.

Research output: Contribution to journalArticle

Chen, X, Wales, P, Quinti, L, Zuo, F, Moniot, S, Herisson, F, Rauf, NA, Wang, H, Silverman, RB, Ayata, C, Maxwell, MM, Steegborn, C, Schwarzschild, MA, Outeiro, TF & Kazantsev, AG 2015, 'The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia', PLoS One, vol. 10, no. 1, e0116919. https://doi.org/10.1371/journal.pone.0116919
Chen, Xiqun ; Wales, Pauline ; Quinti, Luisa ; Zuo, Fuxing ; Moniot, Sébastien ; Herisson, Fanny ; Rauf, Nazifa Abdul ; Wang, Hua ; Silverman, Richard B. ; Ayata, Cenk ; Maxwell, Michelle M. ; Steegborn, Clemens ; Schwarzschild, Michael A. ; Outeiro, Tiago F. ; Kazantsev, Aleksey G. / The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia. In: PLoS One. 2015 ; Vol. 10, No. 1.
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