Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease.
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ABSTRACT:
SUBMITTER: Yacoubian TA
PROVIDER: S-EPMC2998343 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:14-3-3 proteins are key regulators of cell survival. We have previously demonstrated that 14-3-3 levels are decreased in an alpha-synuclein (αsyn) mouse model of Parkinson's disease (PD), and that overexpression of certain 14-3-3 isoforms is protective in several PD models. Here we examine whether changes in 14-3-3 phosphorylation may contribute to the neurodegenerative process in PD. We examine three key 14-3-3 phosphorylation sites that normally regulate 14-3-3 function, including serine 58 (S58), serine 184 (S184), and serine/threonine 232 (S/T232), in several models of PD and in human PD brain. We observed that an increase in S232 phosphorylation is observed in rotenone-treated neuroblastoma cells, in cells overexpressing αsyn, and in human PD brains. Alterations in S58 phosphorylation were less consistent in these models, and we did not observe any phosphorylation changes at S184. Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on αsyn. Mutation of the S232 site affected 14-3-3θ's neuroprotective effects against rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), with the S232D mutant lacking any protective effect compared to wildtype or S232A 14-3-3θ. The S232D mutant partially reduced the ability of 14-3-3θ to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD.
| S-EPMC4458424 | biostudies-literature
Project description:ObjectiveParkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, no definitive cure or effective disease-modifying treatment for PD exists to date. Therefore, the identification of novel therapeutic agents with neuroprotective properties is of utmost importance. Here, we aimed to investigate the potential neuroprotective effects of Carpesii fructus extract (CFE) in both cellular and Caenorhabditis elegans (C. elegans) models of PD.MethodsThe neuroprotective effect of CFE in H2O2- or 6-OHDA-induced PC-12 cells and α-synuclein-overexpressing PC-12 cells were investigated by determining the cell viability, mitochondrial damage, reactive oxygen species (ROS) production, apoptosis, and α-synuclein expression. In NL5901, BZ555, and N2 worms, the expression of α-synuclein, motive ability, the viability of dopaminergic neurons, lifespan, and aging-related phenotypes were investigated. The signaling pathway was detected by Western blotting and validated by employing small inhibitors and RNAi bacteria.ResultsIn cellular models of PD, CFE significantly attenuated H2O2- or 6-OHDA-induced toxicity, as evidenced by increased cell viability and reduced apoptosis rate. In addition, CFE treatment suppressed ROS generation and restored mitochondrial membrane potential, highlighting its potential as a mitochondrial protective agent. Furthermore, CFE reduced the expression of α-synuclein in wide type (WT)-, A53T-, A30P-, or E46K-α-synuclein-overexpressing PC-12 cells. Our further findings reveal that CFE administration reduced α-synuclein expression and improved its induced locomotor deficits in NL5901 worms, protected dopaminergic neurons against 6-OHDA-induced degeneration in BZ555 worms, extended lifespan, delayed aging-related phenotypes, and enhanced the ability of stress resistance in N2 worms. Mechanistic studies suggest that the neuroprotective effects of CFE may involve the modulation of the MAPK signaling pathway, including ERK, JNK, and p38, whereas the interference of these pathways attenuated the neuroprotective effect of CFE in vitro and in vivo.ConclusionOverall, our study highlights the potential therapeutic value of CFE as a neuroprotective agent in the context of PD. Furthermore, elucidation of the active compounds of CFE will provide valuable insights for the development of novel therapeutic strategies for PD.
| S-EPMC11017466 | biostudies-literature
Project description:Background and purposePrevious findings have indicated that a cannabinoid, such as Δ(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson's disease (PD).Experimental approachThe ability of Δ(9)-THCV to reduce motor inhibition and provide neuroprotection was investigated in rats lesioned with 6-hydroxydopamine and in mice lesioned with lipopolysaccharide (LPS).Key resultsAcute administration of Δ(9)-THCV attenuated the motor inhibition caused by 6-hydroxydopamine, presumably through changes in glutamatergic transmission. Moreover, chronic administration of Δ(9)-THCV attenuated the loss of tyrosine hydroxylase-positive neurones caused by 6-hydroxydopamine in the substantia nigra, through an effect related to its antioxidant properties (it was reproduced by cannabidiol -enriched botanical extract). In addition, CB(2) receptor-deficient mice responded to 6-hydroxydopamine in a similar manner to wild-type animals, and CB(2) receptors were poorly up-regulated in the rat substantia nigra in response to 6-hydroxydopamine. By contrast, the substantia nigra of mice that had been injected with LPS exhibited a greater up-regulation of CB(2) receptors. In these animals, Δ(9)-THCV also caused preservation of tyrosine hydroxylase-positive neurones. This effect probably involved CB(2) receptors as it was also elicited by the selective CB(2) receptor agonist, HU-308, and CB(2) receptor-deficient mice were more vulnerable to LPS lesions. CONCLUSIONS AND IMPLICATIONS Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms.
| S-EPMC3165958 | biostudies-literature
Project description:Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines including dopamine (DA). MAO expression is elevated in Parkinson's disease (PD). An increase in MAO activity is closely related to age, and this may induce neuronal degeneration in the brain due to oxidative stress. MAO (and particularly monoamine oxidase B (MAO-B)) participates in the generation of reactive oxygen species (ROS), such as hydrogen peroxide that are toxic to dopaminergic cells and their surroundings. Although the polyphenol-rich aqueous walnut extract (JSE; an extract of Juglandis Semen) has been shown to have various beneficial bioactivities, no study has been dedicated to see if JSE is capable to protect dopaminergic neurons against neurotoxic insults in models of PD. In the present study we investigated the neuroprotective potential of JSE against 1-methyl-4-phenylpyridinium (MPP⁺)- or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicities in primary mesencephalic cells and in a mouse model of PD. Here we show that JSE treatment suppressed ROS and nitric oxide productions triggered by MPP⁺ in primary mesencephalic cells. JSE also inhibited depletion of striatal DA and its metabolites in vivo that resulted in significant improvement in PD-like movement impairment. Altogether our results indicate that JSE has neuroprotective effects in PD models and may have potential for the prevention or treatment of PD.
| S-EPMC4730349 | biostudies-literature
Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1-39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson's disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD.
| S-EPMC3877910 | biostudies-literature
Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is still no cure for it. PD is characterized by the degeneration of dopaminergic neurons, and oxidative stress has been considered an important pathological mechanism. Therefore, the discovery of antioxidants to alleviate the oxidative damage of dopaminergic neurons is a promising therapeutic strategy for PD. First, a network pharmacology approach was used, and nine common core targets of galangin and PD were screened, mainly involving cell aging, apoptosis, and cellular responses to hydrogen peroxide and hypoxia. In addition, the Gene Ontology (GO) function and pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified apoptosis, PI3K/Akt, and HIF-1 signaling pathways. Furthermore, the molecular docking results revealed a strong affinity between galangin and the NFE2L2/Nrf2 protein. To validate the above predictions, we employed 6-hydroxydopamine (6-OHDA) to induce neuronal death in HT22 cells and Caenorhabditis elegans (C. elegans). MTT, cell morphology observation, and Hoechst 33342-PI staining results showed that galangin significantly increased the viability of 6-OHDA-treated HT22 cells. In addition, galangin inhibited 6-OHDA-induced ROS generation and apoptosis in HT22 cells. Mechanistic studies demonstrated that galangin activates the Nrf2/Keap1 signaling pathway, as evidenced by the decreased protein expression of Keap1 and increased protein expression of Nrf2 and HO-1. In the 6-OHDA-induced PD model of C. elegans, galangin indeed inhibited the degeneration of dopaminergic neurons, improved behavioral ability, and decreased ROS generation. In conclusion, the current study is the first to show that galangin has the capacity to inhibit neuronal degeneration via the Nrf2/Keap1 pathway, suggesting that galangin is a possible PD treatment.
| S-EPMC9413091 | biostudies-literature
Project description:Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Orexin-A is involved in many biological effects of the body. It has been reported that orexin-A has protective effects in cellular models of PD. However, little is known about the protective effects of orexin-A in animal parkinsonian models and the cellular mechanism has not yet been fully clarified. The aim of this study was to evaluate the effects of orexin-A in MPTP mice model of PD as well as the possible neuroprotective mechanisms of orexin-A on dopaminergic neurons. The results from animal experiments demonstrated that orexin-A attenuated the loss of dopaminergic neurons and the decrease of tyrosine hydroxylase (TH) expression in the substantia nigra, normalized the striatal dopaminergic fibers, and prevented the depletion of dopamine and its metabolites in the striatum. MPTP-treated mice showed cognitive impairments accompanied with significant motor deficiency. Orexin-A improved MPTP-induced impairments in both motor activity and spatial memory. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor (BDNF) in dopaminergic neurons of the substantia nigra. Furthermore, the protective effects of orexin-A on MPTP parkinsonian mice could be blocked by orexinergic receptor 1 (OX1R) antagonist, SB334867. In another set of experiments with SH-SY5Y dopaminergic cells, orexin-A significantly induced the expression of BDNF in a dose and time-dependent manner. The upregulation of BDNF is mainly concerned with PI3K and PKC signaling pathways via OX1R. The present study demonstrated that orexin-A exerted neuroprotective effects on MPTP parkinsonian mice, which may imply orexin-A as a potential therapeutic target for PD.
| S-EPMC6262320 | biostudies-literature
Project description:BackgroundParkinson's disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.MethodsBoth pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin.ResultsOral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD.ConclusionsCollectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.
| S-EPMC3488558 | biostudies-literature
Project description:Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. In addition, the neuroprotective effect of TGY was also evaluated in the human dopaminergic neuroblastoma SH-SY5Y cell line treated with rotenone and the rotenone intoxicated hemi-parkinsonian rats. In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. Conclusively, TGY is neuroprotective in PD models both in vivo and in vitro.
| S-EPMC4649620 | biostudies-other
Project description:14-3-3s represent a family of highly conserved 30 kDa acidic proteins. 14-3-3s recognize and bind specific phospho-sequences on client partners and operate as molecular hubs to regulate their activity, localization, folding, degradation, and protein-protein interactions. 14-3-3s are also associated with the pathogenesis of several diseases, among which Parkinson's disease (PD). 14-3-3s are found within Lewy bodies (LBs) in PD patients, and their neuroprotective effects have been demonstrated in several animal models of PD. Notably, 14-3-3s interact with some of the major proteins known to be involved in the pathogenesis of PD. Here we first provide a detailed overview of the molecular composition and structural features of 14-3-3s, laying significant emphasis on their peculiar target-binding mechanisms. We then briefly describe the implication of 14-3-3s in the central nervous system and focus on their interaction with LRRK2, α-Synuclein, and Parkin, three of the major players in PD onset and progression. We finally discuss how different types of small molecules may interfere with 14-3-3s interactome, thus representing a valid strategy in the future of drug discovery.
| S-EPMC8455551 | biostudies-literature