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Activation of the ATF2/CREB-PGC-1 alpha pathway by metformin leads to dopaminergic neuroprotection

Title
Activation of the ATF2/CREB-PGC-1 alpha pathway by metformin leads to dopaminergic neuroprotection
Authors
Kang, HojinKhang, RinHam, SangwooJeong, Ga RamKim, HyojungJo, MinkyungLee, Byoung DaeLee, Yun IlJo, AreumPark, ChiHuKim, HyeinSeo, JeongkonPaek, Sun HaLee, Yun-SongChoi, Jeong-YunLee, YunjongShin, Joo-Ho
DGIST Authors
Lee, Yun Il
Issue Date
2017-07
Citation
Oncotarget, 8(30), 48603-48618
Type
Article
Article Type
Article
Keywords
2 PartsAlpha SynucleinBrainDopaminergicDopaminergicGerotargetKnockout MiceMetforminMetforminMitochondriaMitochondriaMouse ModelMPTPParkinson&aposs DiseaseParkinson&aposs DiseasePGC 1 AlphaPGC 1 AlphaPGC 1 AlphaPhosphorylationProtein Kinase
ISSN
1949-2553
Abstract
Progressive dopaminergic neurodegeneration is responsible for the canonical motor deficits in Parkinson's disease (PD). The widely prescribed anti-diabetic medicine metformin is effective in preventing neurodegeneration in animal models; however, despite the significant potential of metformin for treating PD, the therapeutic effects and molecular mechanisms underlying dopaminergic neuroprotection by metformin are largely unknown. In this study, we found that metformin induced substantial proteomic changes, especially in metabolic and mitochondrial pathways in the substantia nigra (SN). Consistent with this data, metformin increased mitochondrial marker proteins in SH-SY5Y neuroblastoma cells. Mitochondrial protein expression by metformin was found to be brain region specific, with metformin increasing mitochondrial proteins in the SN and the striatum, but not the cortex. As a potential upstream regulator of mitochondria gene transcription by metformin, PGC-1α promoter activity was stimulated by metformin via CREB and ATF2 pathways. PGC-1α and phosphorylation of ATF2 and CREB by metformin were selectively increased in the SN and the striatum, but not the cortex. Finally, we showed that metformin protected dopaminergic neurons and improved dopamine-sensitive motor performance in an MPTP-induced PD animal model. Together these results suggest that the metformin-ATF2/CREBPGC- 1α pathway might be promising therapeutic target for PD. © Kang et al.
URI
http://hdl.handle.net/20.500.11750/4404
DOI
10.18632/oncotarget.18122
Publisher
Impact Journals LLC
Files:
There are no files associated with this item.
Collection:
Well Aging Research Center1. Journal Articles


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