Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 as a Neuroprotective Agent: Promotion of the Morphological Developm
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ORIGINAL PAPER
Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 as a Neuroprotective Agent: Promotion of the Morphological Development of Midbrain Dopaminergic Neurons Louise M. Collins • Gerard W. O’Keeffe • Caitriona M. Long-Smith • Sean L. Wyatt • Aideen M. Sullivan • Andre´ Toulouse • Yvonne M. Nolan
Received: 29 November 2012 / Accepted: 5 April 2013 / Published online: 13 April 2013 Ó Springer Science+Business Media New York 2013
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
L. M. Collins G. W. O’Keeffe C. M. Long-Smith A. M. Sullivan A. Toulouse Y. M. Nolan (&) Department of Anatomy and Neuroscience, University College Cork, Western Gate Building, Cork, Ireland e-mail: [email protected] S. L. Wyatt Molecular Biosciences Research Division, School of Biosciences, Life Sciences Building, Museum Avenue, Cardiff CF10 3AT, UK
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. Keywords MKP-1 Dopaminergic neuron p38 6-OHDA Growth Development
Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the selective loss of midbrain dopaminergic neurons from the substantia nigra (SN). This leads to gradual degeneration of the nigrostriatal pathway resulting in primary motor and eventually secondary cognitive and psychiatric symptoms. However, despite intensive research, the aetiology of the disease still remains unclear and a cure remains elusive. Because of the specific loss of dopaminergic neurons in a discreet region of t
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