CK2 Oppositely Modulates l-DOPA-Induced Dyskinesia via Striatal Projection Neurons Expressing D1 or D2 Receptors

Cortés, Marisol; Malave, Lauren; Castello, Julia; Flajolet, Marc; Cenci, M. Angela; Friedman, Eitan; Rebholz, Heike

doi:10.1523/jneurosci.0443-17.2017

Cited by 22 publications

(20 citation statements)

References 74 publications

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“…The sensitivity of dSPNs during LID is well established and leads to elevated signaling within the MAPK and cAMP/PKA pathways 24,28 . In particular, the amount of pERK positive cells in D1 SPNs in the striatum correlates with dyskinesia severity 28 , while a correlation is not necessary for PKA substrate phosphorylation 49,50 . Ding et al showed that repeated L-DOPA administration leads to ERK phosphorylation in CINs which underlies higher basal firing and potentiated excitatory responses to DA in CINs concomitant with LID expression 32 .…”

Section: Discussionmentioning

confidence: 99%

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Castello

Cortés

Malave

et al. 2020

Sci Rep

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The dopamine D5 receptor (D5R) is a Gα s-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, it affects up to 4% of people aged 65 years or more 1. Hallmarks of the disorder are motor symptoms such as tremor, rigidity, bradykinesia and gait disturbances 2 , which are a result of the selective degeneration of dopaminergic neurons within the substantia nigra pars compacta and thus not by but of dopamine depletion 3. Up to today, L-DOPA treatment remains the gold standard treatment for PD. In the majority of patients, the efficacy of L-DOPA is reduced and debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), develop during chronic L-DOPA treatment over several years 4. Various pharmacological tools are currently investigated with the aim to mitigate these complications. The striatum is comprised mainly by two types of GABAergic projection neurons (SPNs) that are categorized based on their predominant expression of either D1-or D2 receptors, together making up over 95% of all striatal neurons 5. The spiny neurons that project directly to the basal ganglia output nuclei are termed 'direct pathway' or dSPNs and express D1 receptor (D1R), that signals via the G proteins Gα s /Gα olf to PKA and enhances cAMP production. The other class of projection neurons is termed 'indirect pathway' or iSPNs, and they express the inhibitory, Gα i/o-coupled D2 receptor (D2R) 6 , leading to less cAMP being produced. The balance between the two pathways is crucial for voluntary movement control and is disturbed in PD. In addition, cholinergic interneurons (CINs), which represent 1-3% of striatal neurons but are extensively arborized, gat...

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Section: Discussionmentioning

confidence: 99%

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Castello

Cortés

Malave

et al. 2020

Sci Rep

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“…S1b ). These mechanisms are quite different from those of current small molecular regulators, which directly activate DRD1/D2 [ 44 ]. However, the molecular mechanism by which DRD mRNA expression is regulated still needs to be explored.…”

Section: Discussionmentioning

confidence: 91%

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Wang

Cui

et al. 2019

Acta Pharmacol Sin

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Microglia-mediated neuroinflammation is a crucial risk factor for neurological disorders. Recently, dopamine receptors have been found to be involved in multiple immunopathological processes and considered as valuable therapeutic targets for inflammation-associated neurologic diseases. In this study we investigated the anti-neuroinflammation effect of isosibiricin, a natural coumarin compound isolated from medicinal plant Murraya exotica . We showed that isosibiricin (10−50 μM) dose-dependently inhibited lipopolysaccharide (LPS)-induced BV-2 microglia activation, evidenced by the decreased expression of inflammatory mediators, including nitrite oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and interleukin-18 (IL-18). By using transcriptomics coupled with bioinformatics analysis, we revealed that isosibiricin treatment mainly affect dopamine receptor signalling pathway. We further demonstrated that isosibiricin upregulated the expression of dopamine D1/2 receptors in LPS-treated BV-2 cells, resulting in inhibitory effect on nucleotide binding domain-like receptor protein 3 (NLRP3)/caspase-1 inflammasome pathway. Treatment with dopamine D1/2 receptor antagonists SCH 23390 (1 μM) or sultopride (1 μM) could reverse the inhibitory effects of isosibiricin on NLRP3 expression as well as the cleavages of caspase-1 and IL-1β. Collectively, this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.

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“…CK2 kinases are highly expressed in the brain, with a clear predominance of CK2α over CK2α' (Ceglia et al 2011). Using conditional CK2α knockout mice, we showed that CK2α is a modulator of receptor endocytosis and neurotransmitter signaling, in particular of Gα s -coupled receptors such as D1, A2a and 5-HT4 receptors (Castello et al 2017;Cortes et al 2017;Rebholz et al 2009;Rebholz et al 2013). For example, Drd1a-Cre CK2α knockout mice lacking CK2α in striatal direct medium spiny neurons exhibit characteristics that partially phenocopy OCNDS.…”

Section: Introductionmentioning

confidence: 94%

Okur-Chung Neurodevelopmental Syndrome-linked CK2α mutations have reduced kinase activity

Domı́nguez

Gamero

Corasolla

et al. 2021

Preprint

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The Okur-Chung Neurodevelopmental Syndrome, or OCNDS, is a newly discovered rare neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, epilepsy and language/verbalization deficits. OCNDS is linked to de novo variants in CSNK2A1, that lead to missense or deletion/truncating mutations in the encoded protein, the protein kinase CK2a. Eighteen different missense CK2a mutants have been identified to date, however no biochemical or cell biological studies have yet been performed to clarify the functional impact of such mutations. Here, we show that 15 different missense CK2a mutations lead to varying degrees of loss of kinase activity as recombinant purified proteins and when mutants are ectopically expressed in mammalian cells. We further detect changes in the phosphoproteome of three patient derived fibroblast lines and show that the subcellular localization of CK2a is altered for some of the OCNDS-linked mutants and in patient derived fibroblasts. Our data argue that reduced kinase activity and abnormal localization of CK2a may underlie the OCNDS phenotype.

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CK2 Oppositely Modulates l-DOPA-Induced Dyskinesia via Striatal Projection Neurons Expressing D1 or D2 Receptors

Cited by 22 publications

References 74 publications

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Okur-Chung Neurodevelopmental Syndrome-linked CK2α mutations have reduced kinase activity

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