Journal
NEUROMOLECULAR MEDICINE
Volume 15, Issue 2, Pages 435-446Publisher
HUMANA PRESS INC
DOI: 10.1007/s12017-013-8230-5
Keywords
MKP-1; Dopaminergic neuron; p38; 6-OHDA; Growth; Development
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Funding
- College of Medicine and Health, University College Cork
- Science Foundation Ireland [SFI/RFP/NSC1298, 10/RFP/NES2786]
- Irish Research Council for Science Engineering and Technology
- Science Foundation Ireland (SFI) [10/RFP/NES2786] Funding Source: Science Foundation Ireland (SFI)
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A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.
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