Conference Contribution Details
Mandatory Fields
Collins L.M., O'Keeffe G.W., Long-Smith C.M., Sullivan A.M., Toulouse A., Nolan Y.M.
7th Neuroscience Ireland Annual Conference
Mitogen-activated protein kinase phosphatase (Mkp)-1 promotes the morphological development of midbrain dopaminergic neurons
Royal College of Surgeons Ireland
Invited Lectures (Conference)
2012
()
1
Optional Fields
05-SEP-12
06-SEP-12
                          

PD is a progressive neurodegenerative disorder characterised by the loss of midbrain dopaminergic neurons from the substantia nigra (SN) resulting in motor, cognitive and psychiatric symptoms. Mitogen-activated protein kinases (MAPKs), such as p38, Erk and JNK, are instrumental in orchestrating a variety of cellular processes and are activated by hormones, growth factors, cytokines and environmental stresses. MKPs provide a negative feedback mechanism for regulating MAPK activity by de-phosphorylating up-stream kinases. MKP-1 de-phosphorylates all classes of MAPKs and preferentially de-phosphorylates p38. MKP-1 has been shown to be essential for BDNF-induced axon branching and may be an essential regulator of synaptogenesis [1].  Overexpression of MKP-1 has recently been shown to prevent neuronal death in a model of acute cerebral infarction [2].

We examined a role for MKP-1 in regulating the growth of dopaminergic neurons during development and investigated whether its overexpression protects the cytoarchitecture of these cells from 6-hydroxydopamine (6-OHDA)-induced degeneration using the E14 rat ventral mesencephalon (VM) in vitro model system.

Immunohistochemical analysis revealed that MKP-1 was expressed under basal conditions in the adult rat SN in vivo and co-localised with TH+-neurons. To assess the function of MKP-1, E14 rat VM cultures were electroporated with a control plasmid or an MKP-1 plasmid together with a PCX-GFP plasmid to visualise transfected cells. We found a significant increase in total neurite length (n=3; p< 0.01) and total neuronal branching (n=3; p< 0.01) in MKP-1-transfected cultures at 3 DIV, when compared to control-transfected cultures. Sholl analysis also revealed that MKP-1 overexpression enhanced neuronal complexity at 3 DIV (n=3; p< 0.05). Dopaminergic neurons overexpressing MKP-1 were more complex than their control counterparts in vitro. Specifically, MKP-1-transfected dopaminergic neurons demonstrated a significant increase in total neurite length (n=3; p< 0.01) and total neuronal branching (n=3; p< 0.001) with a maximum increase observed at the level of primary branches (n=3; p< 0.01). We demonstrated that 6-OHDA inhibited neurite growth of TH+-neurons through activation of p38 signalling which was attenuated by the phospho-p38 inhibitor, SB203580. Overexpressing MKP-1 in dopaminergic neurons was neuroprotective against the effects of 6-OHDA.

Collectively, these findings show that MKP-1 is expressed by dopaminergic neurons, can promote the growth and elaboration of their neural process and can protect them from the neurotoxic effects of 6-OHDA.  As such, strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting midbrain dopaminergic neurons in the context of PD.