title: Mitogen-activated protein kinase phosphatase (MKP)-1 as a neuroprotective agent: promotion of the morphological development of midbrain dopaminergic neurons.
abstract: 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.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Western Gate Building, Cork, Ireland.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Collins
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: Long-Smith
authors.forename: Sean L
authors.initials: SL
authors.lastname: Wyatt
authors.forename: Aideen M
authors.initials: AM
authors.lastname: Sullivan
authors.forename: André
authors.initials: A
authors.lastname: Toulouse
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Nolan
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D007093:Imidazoles / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D016501:Neurites / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D007093:Imidazoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011725:Pyridines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016627:Oxidopamine; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; C093642:SB 203580