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
. Overexpression of MKP-1 has recently been
shown to prevent neuronal death in a model of acute
cerebral infarction .
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.
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.
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.