cAMP Response Element Binding-Protein- and Phosphorylation-Dependent Regulation of Tyrosine Hydroxylase by PAK4: Implications for Dopamine Replacement Therapy (original) (raw)
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BackgroundCyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme involved in neuronal development, maturation and survival. CDK5 activity is tightly regulated by association with regulatory proteins p35 and p39. Upon neuronal insults, increased intracellular calcium activates calpain, cleaving p35 into p25, which has a higher affinity for CDK5. p25 hyperactivates CDK5, initiating apoptotic cascades that lead to significant dopaminergic (DAergic) loss that can leads to neurodegenerative disorders, such as Parkinson’s disease (PD).ObjectiveThis study investigates hyperactivation of CDK5/p25 in the 6-hydroxydopamine (6-OHDA) rat model of PD and specific inhibition of CDK5/p25 by truncated peptide 5 (TP5). TP5 was investigated for amelioration of 6-OHDA induced behaviour impairments and significant protection of dopamine neurons through tyrosine hydroxylase (TH).Methods6-OHDA induced motor impairments and reduced TH. Motor assessments included locomotor activity, beam transversal,...
Journal of Biological Chemistry, 2012
Background: DARPP-32 is implicated in L-DOPA-induced dyskinesia. Results: PKA-dependent phosphorylation of DARPP-32 in a distinct subset of striatal neurons is required for L-DOPA-induced activation of ERK and mTORC1. Conclusion: PKA-dependent phosphorylation of DARPP-32 plays a critical role in dyskinesia and associated signaling alterations. Significance: The PKA/DARPP-32 cascade is a key target for the treatment of dyskinesia. 3 The abbreviations used are: MSN, medium spiny neuron; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; DARPP-32, dopamine-and cAMPregulated phosphoprotein of 32 kDa; mTORC1, mammalian target of rapamycin complex 1; LID, L-DOPA-induced dyskinesia; 6-OHDA, 6-hydroxydopamine; AIM, abnormal involuntary movements; rpS6, ribosomal protein S6; ANOVA, analysis of variance; L-DOPA, L-3,4-dihydroxyphenylalanine.
Molecular basis of dopamine replacement therapy and its side effects in Parkinson’s disease
Cell and Tissue Research, 2018
There is currently no cure for Parkinson's disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson's disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.
Brain Sciences
The progressive degradation of the nigrostriatal system leads to the development of Parkinson’s disease (PD). The synthesis of dopamine, the neurotransmitter of the nigrostriatal system, depends on the rate-limiting enzyme, tyrosine hydroxylase (TH). In this study, we evaluated the synthesis of dopamine during periods of neurodegradation and neuroplasticity in the nigrostriatal system on a model of the early clinical stage of PD. It was shown that the concentration of dopamine correlated with activity of TH, while TH activity did not depend on total protein content either in the SN or in the striatum. Both during the period of neurodegeneration and neuroplasticity, TH activity in SN was determined by the content of P19-TH, and in the striatum it was determined by P31-TH and P40-TH (to a lesser extent). The data obtained indicate a difference in the regulation of dopamine synthesis between DA-neuron bodies and their axons, which must be considered for the further development of sympt...
Molecular Pharmacology, 2002
Previous work demonstrated that stimulation of D 2 dopamine receptors (D 2 DRs) in the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat enhanced striatal extracellular signal-regulated kinase (ERK) activity ipsilateral to the lesion. The present work was designed to explore the mechanism underlying the activation of ERK in the denervated striatum. Stimulation of D 2 DR induced a 60% inhibition in protein tyrosine phosphatase (PTP) activity but not in PSP activity in lesioned striata. The D 2 DR antagonist spiperone blocked quinpirole-elicited PTP inhibition, and the D 1 receptor agonist 2,3,4,5-tetrahydro-7,8dihydroxy-1-phenyl-1H-3-benzazepine (SKF38393) did not inhibit PTP activity, indicating that PTP inhibition is a specific effect mediated by stimulation of D 2 DR. We further discovered that striatal mitogen-activated protein kinase phosphatase (MKP), a protein phosphatase that is responsible for ERK de
A Synopsis on the Role of Tyrosine Hydroxylase in Parkinsons Disease
2012
Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of Ldihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either -synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro-and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.
l-DOPA treatment of parkinsonian rats changes the expression of Src, Lyn and PKC kinases
Neuroscience Letters, 2006
The dopamine (DA) precursor l-DOPA remains the most common treatment for Parkinson's disease (PD). However, long-term treatment with l-DOPA induces dyskinesia and motor disabilities in PD patients, indicating that this pharmacological agent is unable to fully compensate for the effects of DA denervation when used chronically. In this study, we examined the effect 6-hydroxydopamine (6-OHDA)-induced DA denervation of the striatum followed by either acute or chronic treatment with l-DOPA on gene expression of critical regulators of glutamate synaptic transmission. We found that administration of l-DOPA in rats with unilateral DA denervation resulted in a progressive increase of contraversive circling behavior and modulated the expression of Src, Lyn and PKC kinases. In particular, acute (3 days) and chronic (21 days) l-DOPA treatment were differentially able to rescue the effects of DA lesion, since only the acute treatment with l-DOPA corrected the decrease in Src, Lyn and PKC kinase expression induced by 6-OHDA lesion. Also, the reduced phosphorylation level of NR1 receptor subunit induced by 6-OHDA was only partially reversed by chronic l-DOPA treatment.
The Journal of Neuroscience, 2000
The striatal-enriched protein tyrosine phosphatase (STEP) family is expressed within dopaminoceptive neurons of the CNS and is particularly enriched within the basal ganglia and related structures. Alternative splicing produces several isoforms that are found in a number of subcellular compartments, including postsynaptic densities of medium spiny neurons. The variants include STEP61, a membrane-associated protein, and STEP46, a cytosolic protein. The C terminals of these two isoforms are identical, whereas the N-terminal domain of STEP61contains a novel 172 amino acid sequence that includes several structural motifs not present in STEP46. Amino acid sequencing revealed a number of potential phosphorylation sites in both STEP isoforms. Therefore, we investigated the role of phosphorylation in regulating STEP activity. Both STEP61and STEP46are phosphorylated on seryl residues by a cAMP-dependent protein kinase (PKA)-mediated pathway in striatal homogenates. The specific residues phos...
Cell Transplantation, 2015
The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages.
Journal of experimental neuroscience, 2018
Dopamine controls various physiological functions in the brain and periphery by acting on its receptors D1, D2, D3, D4, and D5. Dopamine receptors are G protein-coupled receptors involved in the regulation of motor activity and several neurological disorders such as schizophrenia, bipolar disorder, Parkinson's disease (PD), Alzheimer's disease, and attention-deficit/hyperactivity disorder. Reduction in dopamine content in the nigrostriatal pathway is associated with the development of PD, along with the degeneration of dopaminergic neurons in the substantia nigra region. Dopamine receptors directly regulate neurotransmission of other neurotransmitters, release of cyclic adenosine monophosphate, cell proliferation, and differentiation. Here, we provide an update on recent knowledge about the signalling mechanism, mode of action, and the evidence for the physiological and functional basis of dopamine receptors. We also highlight the pivotal role of these receptors in the modul...