When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

Lee, Yi Chao; Yang, Ying; Huang, Chuen Lin; Kuo, Tsun Yung; Lin, Jiunn-Yuan; Yang, De Ming; Huang, Nai Kuei

doi:10.1371/journal.pone.0038865

Cited by 25 publications

(27 citation statements)

References 56 publications

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“…Thus, CGS rescues the corticostriatal synaptic disconnection and progressive motor impairment observed in HD mice (15,50). These findings together with several earlier reports suggest that activation of the A 2A R, a cAMP-elevating receptor, is a therapeutic option in HD and elicits beneficial effects on several key HD symptoms (including formation of intranuclear inclusions, impaired motor coordination, brain atrophy, and urea cycle deficiency) (15,(52)(53)(54). Consistent with the possible beneficial role of the A 2A R in HD, Mievis and colleagues demonstrated that elimination of the A 2A R exacerbated HD progression in a mouse model of HD (55).…”

Section: Figsupporting

confidence: 63%

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

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Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6 S120A ) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6 S120D ) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat in the Huntingtin (HTT) gene. The normal HTT gene has 35 or fewer CAG repeats in its N-terminal region, whereas expansion of the repeat beyond 35 units confers toxicity to the Huntingtin protein (HTT) and evokes HD pathogenesis (1). The major clinical presentations of HD include chorea, cognitive decline, psychiatric symptoms, and a systemic metabolic defect (2). Selective neuronal loss occurs in multiple brain regions, particularly in the striatum and cortex. Since a great number of cellular machineries (including transcription, vesicle transport, molecular chaperones, and the ubiquitin-proteasome system [UPS]) are compromised by the expression of mutant HTT (mHTT) (3), effective removal of mHTT has become one of the most challenging aspects of drug development for HD.The UPS, which degrades misfolded and/or damaged proteins in eukaryotes, is the major regulatory proteolytic pathway. It regulates many essential cellular processes, including transcription, translation, DNA repair, chromatin remodeling, cell survival, signal transduction, protein trafficking, and synaptic plasticity (4). A recent study demonstrated that AAA-ATPase subunits are critical for cell-type-specific regulation of UPS activity (5). Interestingly, UPS activity is under metabolic control. Posttranslational modifications, such as O-GlcNacylation and phosphorylation of 19S subunits, affect the proteolytic activity of the UPS (6). In addition, impaired functioning of the UPS is believed to contribute to the pathogenic processes of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease (PD), and HD. Recent studies revealed that the UPS might be impaired in HD mouse models and patients (7,8). Intriguingly, although the degradation of polyubiquitin-tagg...

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Section: Figsupporting

confidence: 63%

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

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“…In fact, aiming at a treatment against familial dysautonomia, kinetin has been applied to patients at a dose of 23.5 mg/Kg/d for 28 d with promising results [9, 33]. The exogenous application of CKs and their anti-ageing effects for fibroblast cells [34–36], and the interaction between CKs and the adenosine A2A-receptor and its function as novel neuroprotectant [35] and anti-inflammatory [37] agent with immune suppressive effects have interesting immunomodulatory implications for human cells. Quite intriguingly and apart from the external application/addition of CKs to mammalian cells a recent finding on the regulation of LOG-like protein (CK-activating enzyme) by the animal pathogen M .…”

Section: Resultsmentioning

confidence: 99%

The Plant Hormone Cytokinin Confers Protection against Oxidative Stress in Mammalian Cells

et al. 2016

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Modulating key dynamics of plant growth and development, the effects of the plant hormone cytokinin on animal cells gained much attention recently. Most previous studies on cytokinin effects on mammalian cells have been conducted with elevated cytokinin concentration (in the μM range). However, to examine physiologically relevant dose effects of cytokinins on animal cells, we systematically analyzed the impact of kinetin in cultured cells at low and high concentrations (1nM-10μM) and examined cytotoxic and genotoxic conditions. We furthermore measured the intrinsic antioxidant activity of kinetin in a cell-free system using the Ferric Reducing Antioxidant Power assay and in cells using the dihydroethidium staining method. Monitoring viability, we looked at kinetin effects in mammalian cells such as HL60 cells, HaCaT human keratinocyte cells, NRK rat epithelial kidney cells and human peripheral lymphocytes. Kinetin manifests no antioxidant activity in the cell free system and high doses of kinetin (500 nM and higher) reduce cell viability and mediate DNA damage in vitro. In contrast, low doses (concentrations up to 100 nM) of kinetin confer protection in cells against oxidative stress. Moreover, our results show that pretreatment of the cells with kinetin significantly reduces 4-nitroquinoline 1-oxide mediated reactive oxygen species production. Also, pretreatment with kinetin retains cellular GSH levels when they are also treated with the GSH-depleting agent patulin. Our results explicitly show that low kinetin doses reduce apoptosis and protect cells from oxidative stress mediated cell death. Future studies on the interaction between cytokinins and human cellular pathway targets will be intriguing.

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“…[2][3][4] Interestingly, the cytokinin zeatin riboside has been shown to activate adenosine A 2A receptor signaling in a mammalian neuronal cell line. 5 Although the expression of the Gs-coupled A 2A R varies widely by mammalian cell type, it is known to be broadly expressed by immune system cells, with the activation of the A 2A R playing a role in terminating inflammation via the regulation of cells involved in innate and adaptive immunity. 6 Given the adenosine-based structure of zeatin riboside, its activity as an A 2A R agonist is not entirely surprising; however, it does endow the compound with significant therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

The plant hormone zeatin riboside inhibits T lymphocyte activity via adenosine A2A receptor activation

Lappas

2014

Cell Mol Immunol

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Cytokinins are plant hormones that play an integral role in multiple aspects of plant growth and development. The biological functions of cytokinins in mammalian systems are, however, largely uncharacterized. The naturally occurring cytokinin zeatin riboside has recently been demonstrated to activate the mammalian adenosine A 2A receptor, which is broadly expressed by various cell types including immune system cells, with the activation of the A 2A R playing a role in the regulation of cells involved in both innate and adaptive immunity. We show for the first time that zeatin riboside modulates mammalian immune system activity via an A 2A R-dependent mechanism. Specifically, zeatin riboside treatment induces the production of cyclic adenosine monophosphate (cAMP) by T lymphocytes and inhibits the production by CD31 CD4 1 T cells of interferon (IFN)-c, IL-2, tumor-necrosis factor (TNF)-a, IL-4 and IL-13, and the production by CD31 CD8 1 T cells of IFN-c, IL-2 and TNF-a. Additionally, the upregulation of CD25, CD69 and CD40L by activated T lymphocytes is modulated by zeatin riboside. Zeatin riboside treatment also potently inhibits thioglycollate-induced peritoneal leukocytosis. The immunomodulatory activities of zeatin riboside are blocked by co-treatment with the selective A 2A R antagonist ZM241385. These data suggest that zeatin riboside possesses therapeutic potential as a mammalian immunomodulatory agent.

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When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

Cited by 25 publications

References 56 publications

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

The Plant Hormone Cytokinin Confers Protection against Oxidative Stress in Mammalian Cells

The plant hormone zeatin riboside inhibits T lymphocyte activity via adenosine A2A receptor activation

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