Alpha-Synuclein (Snca) regulates ovariectomy-induced bone loss by altering the expression of genes in specific bone network modules
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68313 | GEO | 2016/12/01
SECONDARY ACCESSION(S): PRJNA282414
REPOSITORIES: GEO
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Project description:The postmenopausal period in women is associated with decreased circulating estrogen levels, which accelerate bone loss and increase the risk of fracture. Here, we gained novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause, using co-expression network analysis. Specifically, we generated a co-expression network consisting of 53 gene modules using expression profiles from intact and OVX mice from a panel of inbred strains. The expression of four modules was altered by OVX, including module 23 whose expression was decreased by OVX across all strains. Module 23 was enriched for genes involved in the response to oxidative stress, a process known to be involved in OVX-induced bone loss. Additionally, module 23 homologs were co-expressed in human bone marrow. Alpha synuclein (Snca) was one of the most highly connected "hub" genes in module 23. We characterized mice deficient in Snca and observed a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the altered expression of specific network modules, including module 23. In summary, the results of this study suggest that Snca regulates bone network homeostasis and ovariectomy-induced bone loss.
| S-EPMC4932518 | biostudies-literature
Project description:The peri- and postmenopausal periods in women are associated with decreases in circulating estrogen levels, marked acceleration of age-related bone loss and increased risk of fracture. However, despite the clinical importance of postmenopausal bone loss, our molecular understanding of this process is incomplete. Here, we used co-expression network analysis to gain novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause. Expression profiles from intact and OVX mice from a panel of inbred strains were used to generate a co-expression network consisting of 29 modules. Genes in network module 25 were decreased by OVX in all strains. Module 25 was enriched for genes involved in the response to oxidative stress, a process known to be an upstream causal factor for OVX-induced bone loss. It was also found that module 25 homologs were co-expressed in human bone marrow and were enriched for genes with evidence of genetic association with bone mineral density (BMD) in women. Alpha synuclein (Snca) was the most highly connected “hub” genes in module 25 and its in vivo knockout resulted in a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the targeted alteration of genes in specific network modules, including module 10. Our results identify a gene module associated with OVX-induced bone loss and demonstrate that Snca regulates ovariectomy-induced bone loss by controlling bone network dynamics.
2016-12-01 | GSE68302 | GEO
Project description:A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk.To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma ?-synuclein levels.Two-tiered analysis.Academic research.Patients and control subjects from the NeuroGenetics Research Consortium.We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma ?-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay.Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (? = .05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P = 1.6 × 10(-12)), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2) = 0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma ?-synuclein levels in patients under an adjusted additive model (P = .005).Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.
| S-EPMC3010848 | biostudies-literature
Project description:SNCA protein product, α-synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson's disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA-AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA-AS1 upregulates both SNCA and α-synuclein and, through RNA-sequencing analysis, we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites' extension and synapses' biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA-AS1 expression leads to the opposite effect. As part of this signature is co-regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA-AS1 or SNCA's overexpression, observing a relevant role for SNCA-AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging-related processes, suggesting that SNCA-AS1 could be a key player in cellular senescence, with implications for aging-related diseases. Indeed, the upregulation of SNCA-AS1 leads to alterations in numerous PD-specific genes, with an impact highly comparable to that of SNCA's upregulation. Our results show that SNCA-AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD.
| S-EPMC8672788 | biostudies-literature
Project description:Prostatic acid phosphatase (PAP), which is secreted by prostate, increases in some diseases such as prostate cancer. PAP is also present in the central nervous system. In this study we reveal that α-synuclein (Snca) gene is co-deleted/mutated in PAP null mouse. It is indicated that mice deficient in transmembrane PAP display neurological alterations. By using immunohistochemistry, cerebellar cortical neurons and zone and stripes pattern were studied in Pap-/- ;Snca-/- mouse cerebellum. We show that the Pap-/- ;Snca-/- cerebellar cortex development appears to be normal. Compartmentation genes expression such as zebrin II, HSP25, and P75NTR show the zone and stripe phenotype characteristic of the normal cerebellum. These data indicate that although aggregation of PAP and SNCA causes severe neurodegenerative diseases, PAP -/- with absence of the Snca does not appear to interrupt the cerebellar architecture development and zone and stripe pattern formation. These findings question the physiological and pathological role of SNCA and PAP during cerebellar development or suggest existence of the possible compensatory mechanisms in the absence of these genes.
| S-EPMC6738605 | biostudies-literature
Project description:The activity of protein kinases IKK-? and TANK-binding kinase 1 (TBK1) has been shown to be associated with inflammatory diseases. As an inhibitor of IKK-? and TBK1, amlexanox is an anti-inflammatory, anti-allergic, immunomodulator and used for treatment of ulcer, allergic rhinitis and asthma in clinic. We hypothesized that amlexanox may be used for treatment of osteoclast-related diseases which frequently associated with a low grade of systemic inflammation. In this study, we investigated the effects of amlexanox on RANKL-induced osteoclastogenesis in vitro and ovariectomy-mediated bone loss in vivo. In primary bone marrow derived macrophages (BMMs), amlexanox inhibited osteoclast formation and bone resorption. At the molecular level, amlexanox suppressed RANKL-induced activation of nuclear factor-?B (NF-?B), mitogen-activated protein kinase (MAPKs), c-Fos and NFATc1. Amlexanox decreased the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. Moreover, amlexanox enhanced osteoblast differentiation of BMSCs. In ovariectomized (OVX) mouse model, amlexanox prevented OVX-induced bone loss by suppressing osteoclast activity. Taken together, our results demonstrate that amlexanox suppresses osteoclastogenesis and prevents OVX-induced bone loss. Therefore, amlexanox may be considered as a new therapeutic candidate for osteoclast-related diseases, such as osteoporosis and rheumatoid arthritis.
| S-EPMC4559750 | biostudies-literature
Project description:BackgroundCilostazol has been reported to alleviate the metabolic syndrome induced by increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, which is also associated with osteoclast (OC) differentiation. We hypothesized that bone loss might be attenuated via an action on OC by cilostazol.Methodology and principal findingsTo test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vitro, using ?CT and tartrate-resistant acid phosphatase staining, respectively. Cilostazol prevented from OVX-induced bone loss and decreased oxidative stress in vivo. It also decreased the number and activity of OC in vitro. The effect of cilostazol on reactive oxygen species (ROS) occurred via protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor 1, two major effectors of cAMP. Knockdown of NADPH oxidase using siRNA of p47phox attenuated the inhibitory effect of cilostazol on OC formation, suggesting that decreased OC formation by cilostazol was partly due to impaired ROS generation. Cilostazol enhanced phosphorylation of nuclear factor of activated T cells, cytoplasmic 1 (NFAT2) at PKA phosphorylation sites, preventing its nuclear translocation to result in reduced receptor activator of nuclear factor-?B ligand-induced NFAT2 expression and decreased binding of nuclear factor-?B-DNA, finally leading to reduced levels of two transcription factors required for OC differentiation.Conclusions/significanceOur data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.
| S-EPMC4436362 | biostudies-literature
Project description:Loss-of-function mutations in the gene encoding GBA (glucocerebrosidase, β, acid), the enzyme deficient in the lysosomal storage disorder Gaucher disease, elevate the risk of Parkinson disease (PD), which is characterized by the misprocessing of SNCA/α-synuclein. However, the mechanistic link between GBA deficiency and SNCA accumulation remains poorly understood. In this study, we found that loss of GBA function resulted in increased levels of SNCA via inhibition of the autophagic pathway in SK-N-SH neuroblastoma cells, primary rat cortical neurons, or the rat striatum. Furthermore, expression of the autophagy pathway component BECN1 was downregulated as a result of the GBA knockdown-induced decrease in glucocerebrosidase activity. Most importantly, inhibition of autophagy by loss of GBA function was associated with PPP2A (protein phosphatase 2A) inactivation via Tyr307 phosphorylation. C2-ceramide (C2), a PPP2A agonist, activated autophagy in GBA-silenced cells, while GBA knockdown-induced SNCA accumulation was reversed by C2 or rapamycin (an autophagy inducer), suggesting that PPP2A plays an important role in the GBA knockdown-mediated inhibition of autophagy. These findings demonstrate that loss of GBA function may contribute to SNCA accumulation through inhibition of autophagy via PPP2A inactivation, thereby providing a mechanistic basis for the increased PD risk associated with GBA deficiency.
| S-EPMC4824589 | biostudies-literature
Project description:ObjectivesThe first objective of this study was to probe the effects of genkwanin (GKA) on osteoclast. The second goal of this study was to study whether GKA can protect lipopolysaccharide (LPS) and ovariectomized (OVX) induced bone loss.Materials and methodsVarious concentrations of GKA (1 and 10 mg/kg) were injected into mice. Different concentrations of GKA (1 and 5 μM) were used to detect the effects of GKA on osteoclast and osteoblast.Key findingsGKA attenuated the osteoclast differentiation promoted by RANKL and expression of marker genes containing c-fos, ctsk as well as bone resorption related gene Trap and to the suppression of MAPK signaling pathway. In addition, GKA induced BMMs cell apoptosis in vitro. Moreover, GKA prevented LPS-induced and ovariectomized-induced bone loss in mice.ConclusionOur research revealed that GKA had a potential to be an effective therapeutic agent for osteoclast-mediated osteoporosis.
| S-EPMC9260391 | biostudies-literature
Project description:Alpha-synuclein (?-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson's disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27Kip1 (p27) in the regulation of ?-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of ?-SYN. Knock-down of the member of the same family p21Cip1 (p21) also led to increased ?-SYN levels, indicating that p27 and p21 collaborate in the repression of ?-SYN transcription. We demonstrated that this repression is mediated by the transcription factor E2F4 and the member of the retinoblastoma protein family p130 and that it is dependent of Cdk activity. Chromatin immunoprecipitation analysis revealed specific binding sites for p27, p21 and E2F4 in the proximal ?-SYN gene promoter. Finally, luciferase assays revealed a direct action of p27, p21 and E2F4 in ?-SYN gene expression. Our findings reveal for the first time a negative regulatory mechanism of ?-SYN expression, suggesting a putative role for cell cycle regulators in the etiology of synucleinopathies.
| S-EPMC5893246 | biostudies-literature