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.
Highlights
Progressive loss of dopaminergic neuron and accountable motor deficits characterize Parkinson’s disease (PD), the most common neurodegenerative movement disorder [1, 2]
To obtain insight into how metformin affects the brain and mediates potential neuroprotective effects in PD on a global level, we performed label-free proteomics using tissue from the substantia nigra (SN), which contains a significant population of dopaminergic neurons (Figure 1)
We found that metformin-induced proteins were highly enriched in several distinct pathways including metabolism (28%), mitochondria (25%), cytoskeleton (17%), and ubiquitination (8%) (Figures 1C and 1D, Supplementary Table 1)
Summary
Progressive loss of dopaminergic neuron and accountable motor deficits characterize Parkinson’s disease (PD), the most common neurodegenerative movement disorder [1, 2]. Genetic and functional studies on PD-causing gene mutations (i.e., a-synuclein, Parkin, PINK1, LRRK2, and DJ-1) have provided insight into the diverse and varied molecular mechanisms by which dopaminergic dysfunction and degeneration occur [5]. Previous reviews on the molecular pathophysiology of PD [5, 6] indicate that PD genes interact with mitochondria to cause oxidative stress and cell toxicity. Mitochondrial toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone have been well characterized for their ability to recapitulate major PD-related pathologies including mitochondrial dysfunction, oxidative stress, and dopaminergic cell loss in animal models of PD [79]. Mitochondrial dysfunction appears to be involved in major PD-related pathologies
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