Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins.
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ABSTRACT:
SUBMITTER: Giusto E
PROVIDER: S-EPMC8455551 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.
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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 (?syn) 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 ?syn, 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 ?syn. Mutation of the S232 site affected 14-3-3?'s neuroprotective effects against rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), with the S232D mutant lacking any protective effect compared to wildtype or S232A 14-3-3?. The S232D mutant partially reduced the ability of 14-3-3? 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:14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.
| S-EPMC2998343 | biostudies-literature
Project description:Immunizations that target specific types of immune responses are used commonly to prevent microbial infections. However, a range of immune responses may prove necessary to combat the ravages of neurodegenerative diseases. The goal is to eliminate the 'root' cause of neurodegenerative disorders, misfolded aggregated proteins, while harnessing adaptive immune responses to promote neural repair. However, immunization strategies used to elicit humoral immune responses against aberrant brain proteins have yielded mixed success. While specific proteins can be cleared, the failures in halting disease progression revolve, in measure, around adaptive immune responses that promote autoreactive T cells and, as such, induce a meningoencephalitis, accelerating neurodegeneration. Thus, alternative approaches for protein clearance and neural repair are desired. To this end, our laboratories have sought to transform autoreactive adaptive immune responses into regulatory neuroprotective cells in Parkinson's disease. In this context, induction of immune responses against modified brain proteins serves to break immunological tolerance, while eliciting adaptive immunity to facilitate neuronal repair. How to harness the immune response in the setting of Parkinson's disease requires a thorough understanding of the role of immunity in human disease and the ways to modify such immune responses to elicit therapeutic gain. These are discussed in this review.
| S-EPMC3263336 | biostudies-literature
Project description:The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein ?-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth.
| S-EPMC3324922 | biostudies-literature
Project description:Blood serum was used to identify protein biomarkers for diagnosis of Parkinson's disease (PD) using analytically validated quantitative 2D-gel electrophoresis, and single variable and multivariate statistics. Using banked samples from a first medical center, we identified 57 specific protein spot biomarkers with disease-specific abnormal levels in serum of patients with PD, Alzheimer's disease, amyotrophic lateral sclerosis and similar neurodegenerative conditions (337 samples), when compared to age-matched normal controls (132 samples). To further assess their clinical usefulness in Parkinson's disease, we obtained prospective newly drawn blood serum samples from a second (56 PD, 30 controls) and third (6 PD, 48 controls) medical center. The protein concentrations of the 57 biomarkers were assessed by 2D-gel electrophoresis. Stepwise linear discriminant analysis selected a combination of 21 of the 57 as optimal to distinguish PD patients from controls. When applied to the samples from the second site, the 21 proteins had sensitivity of 93.3% (52 of 56 PD correctly classified), specificity of 92.9% (28 of 30 controls correctly classified); 15 of 15 patients with mild, 28 of 30 with moderate to severe symptoms, and all of the 6 PD patients from the third site were correctly classified. Eleven of the 21 proteins showed statistically significant abnormal concentrations in patients with mild symptoms, and 14 in patients with moderate-severe symptoms. The protein identities reflect the heterogeneity of Parkinson's disease, and thus may provide the capability of monitoring the blood for a diverse range of PD pathophysiological mechanisms: cellular degeneration, oxidative stress, inflammation, and transport.
| S-EPMC6703553 | biostudies-literature
Project description:Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at http://minerva.uni.lu/pd_map .
| S-EPMC4153395 | biostudies-literature
Project description:OBJECTIVE:To identify Parkinson's disease (PD)-associated deregulated pathways and genes, to further elucidate the pathogenesis of PD. METHODS:Dataset GSE100054 was downloaded from the Gene Expression Omnibus, and differentially expressed genes (DEGs) in PD samples were identified. Functional enrichment analyses were conducted for the DEGs. The top 10 hub genes in the protein-protein interaction (PPI) network were screened out and used to construct a support vector machine (SVM) model. The expression of the top 10 genes was then validated in another dataset, GSE46129, and a clinical patient cohort. RESULTS:A total of 333 DEGs were identified. The DEGs were clustered into two gene sets that were significantly enriched in 12 pathways, of which 8 were significantly deregulated in PD, including cytokine-cytokine receptor interaction, gap junction, and actin cytoskeleton regulation. The signature of the top 10 hub genes in the PPI network was used to construct the SVM model, which had high performance for predicting PD. Of the 10 genes, GP1BA, GP6, ITGB5, and P2RY12 were independent risk factors of PD. CONCLUSION:Genes such as GP1BA, GP6, P2RY12, and ITGB5 play critical roles in PD pathology through pathways including cytokine-cytokine receptor interaction, gap junctions, and actin cytoskeleton regulation.
| S-EPMC7543192 | biostudies-literature
Project description:BackgroundParkinson's Disease (PD) is the second most frequent degenerative disorder, the risk of which increases with age. A preclinical PD diagnostic test does not exist. We identify PD blood metabolites and metabolic pathways significantly correlated with age to develop personalized age-dependent PD blood biomarkers.ResultsWe found 33 metabolites producing a receiver operating characteristic (ROC) area under the curve (AUC) value of 97%. PCA revealed that they belong to three pathways with distinct age-dependent behavior: glycine, threonine and serine metabolism correlates with age only in PD patients; unsaturated fatty acids biosynthesis correlates with age only in a healthy control group; and, finally, tryptophan metabolism characterizes PD but does not correlate with age.ConclusionsThe targeted analysis of the blood metabolome proposed in this paper allowed to find specific age-related metabolites and metabolic pathways. The model offers a promising set of blood biomarkers for a personalized age-dependent approach to the early PD diagnosis.
| S-EPMC9258166 | biostudies-literature
Project description:The nuclear envelope component proline-rich protein 14 (PRR14) is involved in the nuclear morphological alteration and activation of the mTOR (mammalian target of rapamycin) signaling pathway, and has been repeatedly shown to be upregulated in patients with Parkinson's disease (PD). The aim of this study was to explore whether PRR14 can be used as a potential biomarker for the diagnosis of PD. We compared PRR14 expression in PD patients and normal controls in gene expression omnibus (GEO) data. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to detect PRR14 expression in PD patients and age- and sex-matched controls. The relationship between serum PRR14 and clinical phenotype was evaluated using correlation analysis and logistic regression. The expression of PRR14 in whole blood, substantia nigra, and medial substantia nigra was significantly higher in PD patients than in the healthy control group. Compared to plasma, serum was more suitable for the detection of PRR14. Furthermore, serum PRR14 level in PD patients was significantly higher than that in age- and sex-matched controls. The area under the curve for serum PRR14 level in the ability to identify PD versus age- and sex-matched controls was 0.786. In addition, serum PRR14 level was found to correlate with constipation in PD patients. Our findings demonstrate for the first time that serum PRR14 is a potential biomarker for PD.
| S-EPMC8128746 | biostudies-literature