α-Synuclein promotes H4R3me2s through interacting with BAF-PRMT5 complex
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228331 | GEO | 2023/11/23
REPOSITORIES: GEO
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Project description:α-Synuclein promotes H4R3me2s through interacting with BAF-PRMT5 complex
| PRJNA949282 | ENA
Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor
2014-12-19 | E-GEOD-64304 | biostudies-arrayexpress
Project description:Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected. Factorial design comparing SNCA knock-out mice with wild type littermates in two different tissues (striatum, cerebellum) at two different timepoints (6 and 21 month)
2010-07-21 | E-GEOD-19534 | biostudies-arrayexpress
Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.
2020-09-02 | GSE149632 | GEO
Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.
2013-02-28 | E-GEOD-26532 | biostudies-arrayexpress
Project description:Aggregation of α-synuclein may trigger the development of synucleinopathies, a progressive neurodegenerative disease such as Parkinson's disease and Dementia with Lewy bodies. We demonstrate RNA initiates α-synuclein phase transition in vitro, however, RNA binding ability and its motif remain unclear. Here, we indicate purified human α-synuclein protein preferentially binds to guanine-rich RNA sequences by RNA Bind-N-Seq using a pool of random 24-mer RNA oligonucleotides in vitro. Importantly, these hit motifs were required consecutive guanines not random, suggesting that RNA G-quadruplexes binds to α-synuclein. We also confirmed that GC content and skew of α-synuclein-enriched RNA sequences were similar to that of BG4 (G-quadruplex antibody)-enriched RNA sequences. Taken together, these data suggest that α-synuclein binds to RNA-formed G-quadruplex.
2023-07-17 | GSE235418 | GEO
Project description:We performed RNAseq using whole Drosophila heads after expressing human wild type alpha synuclein in either glia, neurons, or both types. We identified many upregulated genes when alpha synuclein was expresed in glia and many downregulated genes with it was expresed in neurons or both cell types.
2019-09-30 | GSE128120 | GEO
Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation.
2014-12-19 | GSE64304 | GEO
Project description:Recent exon sequencing studies of human tumors have revealed that subunits of mSWI/SNF or BAF complexes are mutated in more than 20% of human malignancies, yet the mechanisms involved in tumor suppression is unclear. BAF chromatin remodeling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb (PcG) across the genome. Several proteins dedicated to this large multi-subunit complex, including SMARCA4 (BRG1) and BAF250A (ARID1A), are mutated at frequencies similar to that of many recognized tumor suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastoma (MB) and greater than 15% of Burkitt's Lymphoma (BL). Here we find a novel function of BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1, as well as the expression of Brg1 point mutants identified in human tumors leads to anaphase bridge formation (sister chromatids linked by catenated strands of DNA), and a G2/M phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα through BAF250a and are required for TopoIIα binding to about 12,000 sites over the genome. Our results indicate that TopoIIα’s chromatin binding is dependent on the ATPase activity of Brg1, which is compromised in oncogenic Brg1 mutants. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumor suppressors. Examination of sites of TopoIIa activity in WT and Brg1-/- ES cells as defined by TopoIIa-DNA covalent adducts formed in the presence of etoposide
2013-03-30 | E-GEOD-45625 | biostudies-arrayexpress
Project description:In order to investigate the effect of Alpha-Ketoglutarate (AKG) on p-α-synuclein in substantia nigra of Parkinson's disease (PD) model mice (C57BL/6), we profiled substantia nigra from wild-type (WT), AAV-α-synuclein (α-Syn), AKG and α-Syn-AKG in male mice by RNA sequencing (RNA-seq).
2022-10-02 | GSE214446 | GEO