Dietary intake of α-ketoglutarate ameliorates α-synuclein pathology in a Parkinson’s disease mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214446 | GEO | 2022/10/02
REPOSITORIES: GEO
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Project description:The goal of this study is to compare gene expression differences between WT and tPA KO mice 4 weeks after overexpression of human alpha-synuclein in the substantia nigra
2022-03-28 | E-MTAB-11567 | biostudies-arrayexpress
Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
2019-08-12 | GSE130683 | GEO
Project description:α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is primarily cytosolic and reversibly interacts with cell membranes. α-Syn also occurs in the nucleus, however, the mechanisms involved in its nuclear localization are poorly understood. We analyzed alterations in gene expression following induced α-Syn expression in SH-SY5Y cells. Analysis for upstream regulators pointed at alterations in transcription activity of retinoic acid receptors (RAR)s and additional nuclear receptors. We show that α-Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of α-Syn is regulated by calreticulin, in a leptomycin-B independent mechanism. Importantly, nuclear translocation of α-Syn following RA treatment enhances its toxicity in cultured neurons and the expression levels of PD-associated genes, among which are two familial PDassociated genes, ATPase cation transporting 13A2 (ATP13A2) and PTEN-induced kinase 1 (PINK1). The results link a physiological role for α-Syn in the regulation of RAmediated gene transcription and its toxicity in the synucleinopathies.
2020-02-24 | GSE145804 | GEO
Project description:Progression through neuronal loss of substantia nigra pars compacta with Parkinson’s disease depends on various protein post-translational modifications mainly comprising phosphorylation, ubiquitination, acetylation, and methylation. Phosphorylation and ubiquitination regulate major physiological changes and cellular signaling pathways during dopaminergic neuronal death. Phosphorylation and ubiquitination dyshomeostasis of substantia nigra pars compacta tissue occurs earlier than movement symptom appearance. Although many phosphorylation and ubiquitination sites have been identified through site-specific methods, systematic quantitative proteomic analysis of pre-symptomatic Parkinson’s disease remains unexplored. Using quantitative proteomics, we have globally profiled ubiquitination and phosphorylation in substantia nigra pars compacta tissue of a Parkinson’s disease transgenic mouse model (A30P*A53T α-synuclein, hm2α-SYN-39 mouse strain) at pre-symptomatic stage; Our datasets of 5,351 phosphorylation sites in 2,136 proteins and 3,971 ubiquitination sites in 1,595 proteins provide valuable insight into pre-symptomatic Parkinson’s disease. After in-depth analysis of the relationship between phosphorylation and ubiquitination sites, we concluded that correlation of the relationship increased with decreasing distance. Subsequent bioinformatic analyses, including gene ontology annotation, domain annotation, subcellular localization, KEGG pathway annotation, functional cluster analysis, and motif analysis were performed to annotate quantifiable targets of phosphorylation and ubiquitination sites. Individual simultaneous phosphorylation and ubiquitination proteins that were differentially quantified were screened. The endocytosis pathway is likely regulated by both phosphorylation and ubiquitination at the molecular protein Epn2 (S439 and K135) in early-stage Parkinson’s disease. Therefore, this elucidation of the dysregulation of phosphorylation and ubiquitination has implications for understanding the pathophysiological mechanism of dopaminergic neuron degeneration and for developing novel therapeutics for Parkinson’s disease.
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Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140264 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140265 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140263 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140269 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
2020-03-23 | GSE140267 | GEO
Project description:Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
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