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

• Published in: Oncotarget 2017-07, Vol.8 (30), p.48603-48618
• Main Authors: Kang, Hojin, Khang, Rin, Ham, Sangwoo, Jeong, Ga Ram, Kim, Hyojung, Jo, Minkyung, Lee, Byoung Dae, Lee, Yun Il, Jo, Areum, Park, ChiHu, Kim, Hyein, Seo, Jeongkon, Paek, Sun Ha, Lee, Yun-Song, Choi, Jeong-Yun, Lee, Yunjong, Shin, Joo-Ho
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 2 - metabolism; Animals; Brain - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cyclic AMP Response Element-Binding Protein - metabolism; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Gene Expression Regulation - drug effects; Humans; Male; Metformin - pharmacology; Mice; Mitochondria - metabolism; Neuroprotective Agents - pharmacology; Parkinson Disease - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Proteomics - methods; Research Paper: Gerotarget (Focus on Aging); Signal Transduction - drug effects; Substantia Nigra - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.18122

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/CREB-PGC-1α pathway might be promising therapeutic target for PD.