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

// Hojin Kang 1,2,* , Rin Khang 1,2,* , Sangwoo Ham 1,* , Ga Ram Jeong 3 , Hyojung Kim 1 , Minkyung Jo 1 , Byoung Dae Lee 3 , Yun Il Lee 4 , Areum Jo 1,2 , ChiHu Park 5,6 , Hyein Kim 1,5 , Jeongkon Seo 7 , Sun Ha Paek 8 , Yun-Song Lee 1 , Jeong-Yun Choi 1 , Yunjong Lee 1 and Joo-Ho Shin 1,2 1 Department of Molecular Cell Biology, Division of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea 2 Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, South Korea 3 Department of Neuroscience, Department of Physiology, Neurodegeneration Control Research Center, Kyung Hee University School of Medicine, Seoul, South Korea 4 Department of New Biology, Daegu Geongbuk Institute of Science and Technology, Daegu, South Korea 5 Research Core Facility, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea 6 HuGeX Co., Ltd. Seongnam, South Korea 7 UNIST Central Research Facility, Ulsan National Institute of Science and Technology, Ulsan, South Korea 8 Department of Neurosurgery, Seoul National University College of Medicine, Seoul, South Korea * These authors have contributed equally to this work Correspondence to: Yunjong Lee, email: // Joo-Ho Shin, email: // Keywords : metformin, dopaminergic, Parkinson’s disease, PGC-1α, mitochondria, Gerotarget Received : October 10, 2016 Accepted : April 24, 2017 Published : May 24, 2017 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/CREB-PGC-1α pathway might be promising therapeutic target for PD.