Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) of the brain. The reduced production and function of neurotrophins (proteins that promote neuronal survival) in PD brains compared to that in normal brains may be a contributing factor in PD. Leptin is a hormone that functions in the hypothalamus to reduce appetite. Leptin receptors are also abundant in dopaminergic neurons in the SNc, leading Weng et al. to investigate whether leptin might play a role in neuronal survival. Immunohistochemical analyses showed that degeneration of mouse dopaminergic neurons in the SNc caused by injection into the brain of the neurotoxin 6-OHDA (a mouse model of PD) was less severe if the mice were pre-injected with leptin. Leptin was also protective against 6-OHDA-induced toxicity in mouse MN9D cells, a dopaminergic cell line. Western blotting assays and treatments with pharmacological inhibitors and short hairpin (sh) RNAs showed that the ability of leptin to block 6-OHDA-induced apoptosis was dependent on leptin receptor-mediated activation of Janus kinase 2 (JAK2), mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and the transcription factor cAMP response element-binding protein (CREB), a known neuronal survival factor. Leptin also stimulated the phosphorylation and nuclear localization of CREB in dopaminergic SNc neurons and increased the abundance of brain-derived neurotrophic factor (BDNF) in the brain compared with that in untreated animals. Together, these data suggest that treatment with leptin may be useful in therapies to combat PD.
Z. Weng, A. P. Signore, Y. Gao, S. Wang, F. Zhang, T. Hastings, X.-M. Yin, J. Chen, Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J. Biol. Chem. 282, 34479-34491 (2007). [Abstract] [Full Text]