Growth/differentiation factor-15 deficiency compromises dopaminergic neuron survival and microglial response in the 6-hydroxydopamine mouse model of Parkinson's disease

Abstract

Growth/differentiation factor-15 (Gdf-15) is a member of the TGF-β superfamily and a pleiotropic, widely distributed cytokine, which has been shown to play roles in various pathologies, including inflammation. Analysis of Gdf-15−/− mice has revealed that it serves the postnatal maintenance of spinal cord motor neurons and sensory neurons. In a previous study, exogenous Gdf-15 rescued 6-hydroxydopamine (6-OHDA) lesioned Gdf-15+/+ nigrostriatal dopaminergic (DAergic) neurons in vitro and in vivo. Whether endogenous Gdf-15 serves the physiological maintenance of nigrostriatal DAergic neurons in health and disease is not known and was addressed in the present study. Stereotactic injection of 6-OHDA into the medial forebrain bundle (MFB) led to a significant decline in the numbers of DAergic neurons in both Gdf-15+/+ and Gdf-15−/− mice over a time-period of 14 days. However, this decrease was exacerbated in the Gdf-15−/− mice, with only 5.5% surviving neurons as compared to 24% in the Gdf-15+/+ mice. Furthermore, the microglial response to the 6-OHDA lesion was reduced in Gdf-15−/− mice, with significantly lower numbers of total and activated microglia and a differential cytokine expression as compared to the Gdf-15+/+ mice. Using in vitro models, we could demonstrate the importance of endogenous Gdf-15 in promoting DAergic neuron survival thus highlighting its relevance in a direct neurotrophic supportive role. Taken together, these results indicate the importance of Gdf-15 in promoting survival of DAergic neurons and regulating the inflammatory response post 6-OHDA lesion.

Keywords

• Gdf-15
• 6-OHDA
• Dopaminergic neurons
• Microglia
• Neurotrophic factors
• Neuroinflammation