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.
Sirtuins are NAD-dependent protein deacetylases that were shown to have beneficial effects against age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. It has been associated with neurodegenerative diseases. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a dopaminergic neurotoxin that replicates most of the clinical features of Parkinson disease (PD) and produces a reliable and reproducible lesion of the nigrostriatal dopaminergic pathway and neurodegeneration after its systemic administration. Chronic administration of MPTP induces lesion via apoptosis. We show here that SIRT2 deacetylates Foxo3a, increases RNA and protein levels of Bim, and as a result, enhances apoptosis in the MPTP model of PD. We also show that neurodegeneration induced by chronic MPTP regimen is prevented by genetic deletion of SIRT2 in mouse. Deletion of SIRT2 leads to the reduction of apoptosis due to an increase in acetylation of Foxo3a and a decrease in Bim levels. We demonstrate that SIRT2 deacetylates Foxo3a, activates Bim, and induces apoptosis only in 1-methyl-4-phenylpyridinium-treated cells. Therefore, designing SIRT2 inhibitors might be helpful to develop effective treatments for PD.
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Lei
L
Liu
Anirudh
A
Arun
Lakia
L
Ellis
Carina
C
Peritore
Gizem
G
Donmez
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects* / Q000494:pharmacology; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009498:Neurotoxins / Q000009:adverse effects* / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011518:Proto-Oncogene Proteins; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D020955:Striatonigral Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011518:Proto-Oncogene Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2