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Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

ABSTRACT: Abstract: Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we utilize UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding for proteins known to interact with postsynaptic AMPA and NMDA receptors. Loci in/near Discs Large MAGUK Scaffold Protein 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P<5x10-8) for BF% and/or BMI. To further evaluate the functional role of PSD-95 (gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PDZ-domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising new therapeutic avenue for sustained weight loss.

ORGANISM(S): Mus musculus

PROVIDER: GSE221549 | GEO | 2024/03/11

REPOSITORIES: GEO

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Project description:Epigenetics presents a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children, despite the relevance of this developmental stage to trajectories of weight gain, because of difficulties obtaining blood tissue samples. This proof of principle study examined DNA methylation in 92 saliva samples, comparing Latino preschool children of normal weight mothers (Body Mass Index [BMI] <27 kg/m2 and WC <90 cm) to children of obese mothers (BMI >30 kg/m2 and WC >100 cm). We hypothesized that salivary DNA methylation patterns in Latino preschool age children born of normal weight vs obese weight mothers would be: 1) associated with maternal BMI phenotype in continuous linear regression analysis; 2) saliva could demonstrate epigenetic variation across individuals; and 3) preschool child saliva would be differentially methylated when comparing those children with obese versus normal weight mothers. One hundred and nineteen CpG sites were significantly (p-value <1.56 X 10-5, p-value adjusted <.05) associated with maternal BMI in linear regression models controlling for childâs age, gender, and BMI. Of these 119 CpG sites, 41 were found within the transcription start site, 5â UTR, 3â UTR, or another regulatory region outside of the gene body. Saliva, a practical human tissue to obtain in naturalistic settings and in pediatric populations, was confirmed to be a viable medium for genome-wide epigenetic testing with maternal weight. Although not identical to results yielded from other human tissue types (i.e., cord blood samples), saliva findings indicate potential epigenetic differences in Latino preschool children at risk for pediatric obesity. This proof of principle study examined DNA methylation in 92 saliva samples, comparing Latino preschool children of normal weight mothers (Body Mass Index [BMI] <27 kg/m2 and WC <90 cm) to children of obese mothers (BMI >30 kg/m2 and WC >100 cm). Antropometry was measured objectively according to a standardized protocol.Saliva from preschool Latino children at risk for obesity (BMI>50% < 95% participating in WIC/SNAP programs) was collected using the Oragene DNA saliva kit following a strict data collection protocol. DNA extraction was performed as per DNA Genotek's recommendations using the PrepIT L2P reagent. Extracted DNA was stored in individually barcoded cryovials at â80 degrees Fahrenheit. For children, saliva was obtained using the âbaby brushâ approach, in which small sponges attached to plastic handles are inserted between cheek and gumline to absorb saliva .Arrays were processed using standard protocol [34], with 3 samples randomly selected to serve as duplicates and 1 sample run with HapMap DNA to test functionality of reagents. Duplicates were measured for high technique consistency with Pearson correlation coefficient (>.99). Methylation data were quality controlled using Illumina GenomeStudio (V2011.1), Methylation module (V1.9.0). Samples with lower than 98% call rate (i.e. <485,000 probes) were excluded. Any non-specific cross-reacting probes, probes carrying common SNPs (MAF >1%), or any probes with p-values greater than 0.05 for more than 20% of the sample were sequentially excluded. Validation via pyrosequencing was conducted.

Project description:PDZ (Post-synaptic density, PSD-95)/ Disc large, Dlg/ Zonula occludens, ZO-1) proteins are central in the assembly of multiprotein signalling complexes that are formed in distinctive, specialized cell regions. In these complexes different signals are orchestrated and traduced into quick and efficient responses controlling cell polarization and cell communication. Viral pathogens target host PDZ proteins by expressing viral proteins containing a PDZ binding motif (PBM). SARS-CoV-1 and -2 harbour the protein E, a viroporin with a conserved PBM in its carboxyl-terminal region. SARS-CoV-1 E protein is a pathogenicity factor that in epithelia interacts with the PDZ protein PALS1, which promote disruption of cell junctions. SARS-CoV-2 infects epithelia, but also cells from the innate immune response, including monocytes, dendritic cells, and alveolar macrophages. Identification of targets of SARS-CoV-2 E protein in immune cells might offer valuable clues to understand how SARS-CoV-2 alters immune response. Here we generated a SARS-CoV-2 E protein fused to a GFP-tag at the amino terminal. This recombinant protein was used as bait to identify associated proteins in THP-1 cells, a human monocytic cell line that can be differentiated to macrophages and dendritic cells. Analysis of the GFP-E protein interactome provided 372 proteins that fall into different functional groups. Only eight of these proteins harbor PDZ domains, including the cell polarity protein ZO-2 and the chemoattractant IL-16. Syntenin, a PDZ protein previously identified as interactor of SARS-CoV-1 E protein in epithelia, was also found in our analysis. Little is known about these PDZ proteins in immune cells, so we addressed their expression in monocytes and along the differentiation towards macrophages and dendritic cells. Our findings support the notion that viral targeting of PDZ proteins alters inflammatory response and highlight the importance of identifying the functions of PDZ proteins into maintenance of immune fitness.

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Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

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