Sirtuin 2 (SIRT2) Enhances 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Nigrostriatal Damage via Deacetylating Forkhead Box O3a (Foxo3a) and Activating Bim Protein

Liu, Lei; Arun, Anirudh; Ellis, Lakia; Peritore, Carina; Dönmez, Gizem

doi:10.1074/jbc.c112.403048

Cited by 46 publications

(27 citation statements)

References 14 publications

(2 reference statements)

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“…While the exact mechanism for reducing α-synuclein-A53T-mediated cell death is not known, these compounds decreased the number but increased the size of α-synuclein aggregates in a cellular model. A recent study validated these observations showing that genetic deletion of SIRT2 is protective in a chemically induced mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 77 . The proposed mechanism is that SIRT2 becomes active as a response to MPTP-induced stress causing Foxo3a deacetylation, which leads to increased levels of the pro-apoptotic factor Bim and neuronal death 77 .…”

Section: Parkinson's Diseasementioning

confidence: 66%

“…A recent study validated these observations showing that genetic deletion of SIRT2 is protective in a chemically induced mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 77 . The proposed mechanism is that SIRT2 becomes active as a response to MPTP-induced stress causing Foxo3a deacetylation, which leads to increased levels of the pro-apoptotic factor Bim and neuronal death 77 . Major mechanisms that have been proposed for SIRT1 and SIRT2 in Parkinson's disease pathogenesis are diagrammed in Figure 3.…”

Section: Parkinson's Diseasementioning

confidence: 66%

“…In PD, SIRT1 can deacetylate heat shock factor 1 (HSF1), which increases hsp70 transcription and decreases the formation of abnormal protein aggregates 11,74,75 . Genetic deletion of SIRT2 is protective in a chemically induced MPTP-model of PD 77 . It is proposed that SIRT2-mediated Foxo3a deacetylation leads to increased levels of the pro-apoptotic factor Bim and neuronal death 77 .…”

Section: Figurementioning

confidence: 98%

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Sirtuin deacetylases in neurodegenerative diseases of aging

2013

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Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.

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Section: Parkinson's Diseasementioning

confidence: 66%

Section: Parkinson's Diseasementioning

confidence: 66%

Section: Figurementioning

confidence: 98%

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Sirtuin deacetylases in neurodegenerative diseases of aging

2013

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“…Sirt2 may also function to regulate autophagy and mitophagy under α-synuclein toxicity [108] . A recent study has shown that Sirt2 enhances MPTPinduced nigrostriatal damage via deacetylating FoxO3a and activating Bim protein [109] . However, this study was recently withdrawn, adding some controversy to the roles of Sirt2 [110] .…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…A recent study has shown that Sirt2 enhances MPTPinduced nigrostriatal damage via deacetylating FoxO3a and activating Bim protein [109] . However, this study was recently withdrawn, adding some controversy to the roles of Sirt2 [110] . As such, further research is warranted.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Sirtuin functions in the brain: From physiological to pathological aspects

Shao

Zhang

Liu

et al. 2014

J. Shanghai Jiaotong Univ. (Sci.)

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Sirtuins are a family of nicotinamide adenine dinucleotide (NAD + ) dependent deacetylases involved in multiple biological functions including metabolism, inflammation, stress resistance and aging. In mammals, there are seven members (Sirt1-Sirt7), with diversities in their subcellular localizations and enzymatic activities. Here, we review the functions of sirtuins, with a focus on their roles in normal brain physiology such as neural development regulation, body homeostasis maintenance, and memory formation. We also discuss the role of sirtuins in a variety of brain diseases including stroke, Alzheimer's, Parkinson's, and motor neuron dysfunction. Because of the emerging functions of sirtuins in brain physiology and pathology, drugs targeting sirtuins may offer potential therapeutic values for brain disorders.

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SIRT2 mediates NADH‐induced increases in Nrf2, GCL, and glutathione by modulating Akt phosphorylation in PC12 cells

et al. 2016

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Edited by Angel Nebreda SIRT2 plays important roles in multiple biological processes. It is unclear whether SIRT2 affects antioxidant capacity by modulating Nrf2, a key transcription factor for multiple antioxidant genes. By studying NADH-treated differentiated PC12 cells, we found that NADH induced a significant increase in the nuclear Nrf2, which was prevented by both SIRT2 siRNA and SIRT2 inhibitor, AGK2. SIRT2 siRNA also blocked the NADH-induced increases in glutamate cysteine ligase (GCL) and glutathione. Moreover, SIRT2 siRNA and AGK2 blocked NADH-induced Akt phosphorylation, and inhibition of Akt phosphorylation prevented NADH-induced increases in the nuclear Nrf2 and glutathione. Collectively, our study shows that SIRT2 regulates nuclear Nrf2 levels by modulating Akt phosphorylation, thus modulating the levels of GCL and total glutathione.

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Sirtuin 2 (SIRT2) Enhances 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Nigrostriatal Damage via Deacetylating Forkhead Box O3a (Foxo3a) and Activating Bim Protein

Cited by 46 publications

References 14 publications

Sirtuin deacetylases in neurodegenerative diseases of aging

Sirtuin deacetylases in neurodegenerative diseases of aging

Sirtuin functions in the brain: From physiological to pathological aspects

SIRT2 mediates NADH‐induced increases in Nrf2, GCL, and glutathione by modulating Akt phosphorylation in PC12 cells

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