Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

Abstract Schizophrenia (SCZ) is highly polygenic, and thousands of genes contribute to its risk. The 145 GWAS loci identified to date do not fully reveal SCZ genetic risk pathways. In this study, we explore a cost-effective strategy to increase power of inference of novel pathways, by expanding the analysis to include sub-threshold GWAS (subGWAS) loci. We identify 180 subGWAS loci (e.g., 5 x10-8 < P ≤ 10-6) based on SCZ summary statistics of 40,675 cases and 64,643 controls from CLOZUK and PGC datasets, and show that subGWAS loci contain substantial true genetic association signals. We merge GWAS (sigGWAS) and subGWAS loci and identify in total 304 high-confidence risk genes (HRGs) by jointly modeling the expanded set of loci. We identify dendrite development and morphogenesis (DDM, GO:0016358 and GO:0048813) as a novel category of biological processes implicated in SCZ genetic risk. SigGWAS loci fail to detect DDM, which is predominantly enriched in subGWAS loci. Further, DDM genes are significantly enriched for heritability of SCZ, as well as bipolar disorder and major depression. Genes in this functional process show cell type specificity in neurons in both fetal and adult brains, and their involvement in SCZ risk is further supported by eQTL analysis of SCZ risk alleles. We derived induced pluripotent stem cell (iPSC) lines from sporadic SCZ patients and normal controls and observe increased neurite lengths and soma sizes in patient-derived iPSC lines along multiple time points during neuronal development, further validating the genetic findings. We also find that the implicated genes are enriched in FDA-approved drug targets, suggesting a therapeutic potential for targeting the implicated biological processes for prevention and treatment. Our results showcase that expanding the analysis to include subGWAS loci is a valuable strategy for enhancing power of uncovering disease mechanisms, especially those of weak effect size, for SCZ and other complex diseases.

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Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Molecules ◽

10.3390/molecules26082118 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2118

Author(s):

Yusuke Hosoya ◽

Junko Ohkanda

Keyword(s):

Drug Targets ◽

Intrinsically Disordered Proteins ◽

Dynamic Control ◽

Disordered Proteins ◽

Biological Processes ◽

Phase Separations ◽

Cellular Processes ◽

Intrinsically Disordered ◽

New Drug ◽

Liquid Phase Separations

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets.

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Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

Science Advances ◽

10.1126/sciadv.abc1428 ◽

2020 ◽

Vol 6 (46) ◽

pp. eabc1428

Author(s):

A. Nakano-Kobayashi ◽

A. Fukumoto ◽

A. Morizane ◽

D. T. Nguyen ◽

T. M. Le ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Neuronal Survival ◽

Disease Model ◽

Neuronal Loss ◽

Induced Pluripotent Stem Cell ◽

Related Factor ◽

Induced Pluripotent ◽

Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

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KRAS Promoter G-Quadruplexes from Sequences of Different Length: A Physicochemical Study

International Journal of Molecular Sciences ◽

10.3390/ijms22010448 ◽

2021 ◽

Vol 22 (1) ◽

pp. 448

Author(s):

Federica D’Aria ◽

Bruno Pagano ◽

Luigi Petraccone ◽

Concetta Giancola

Keyword(s):

Thermodynamic Stability ◽

Drug Targets ◽

Promoter Sequence ◽

Physicochemical Study ◽

Biological Processes ◽

Scanning Calorimetry ◽

Binding Properties ◽

Anticancer Compounds ◽

Nmr Structures ◽

Genomic Regions

DNA G-quadruplexes (G4s) form in relevant genomic regions and intervene in several biological processes, including the modulation of oncogenes expression, and are potential anticancer drug targets. The human KRAS proto-oncogene promoter region contains guanine-rich sequences able to fold into G4 structures. Here, by using circular dichroism and differential scanning calorimetry as complementary physicochemical methodologies, we compared the thermodynamic stability of the G4s formed by a shorter and a longer version of the KRAS promoter sequence, namely 5′-AGGGCGGTGTGGGAATAGGGAA-3′ (KRAS 22RT) and 5′-AGGGCGGTGTGGGAAGAGGGAAGAGGGGGAGG-3′ (KRAS 32R). Our results show that the unfolding mechanism of KRAS 32R is more complex than that of KRAS 22RT. The different thermodynamic stability is discussed based on the recently determined NMR structures. The binding properties of TMPyP4 and BRACO-19, two well-known G4-targeting anticancer compounds, to the KRAS G4s were also investigated. The present physicochemical study aims to help in choosing the best G4 target for potential anticancer drugs.

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Screening of Chloroquine, Hydroxychloroquine and Its Derivatives for Their Binding Affinity to Multiple SARS-CoV-2 Protein Drug Targets

10.26434/chemrxiv.12365282.v1 ◽

2020 ◽

Author(s):

Mallikarjuna Nimgampalle ◽

Vasudharani Devanthan ◽

Ambrish Saxena

Keyword(s):

Binding Affinity ◽

In Silico ◽

Drug Targets ◽

Therapeutic Potential ◽

Viral Proteins ◽

Protein Drug ◽

Potential Treatment ◽

Health Authorities ◽

Derivatives Of

Recently Chloroquine and its derivative Hydroxychloroquine have garnered enormous interest amongst the clinicians and health authorities’ world over as a potential treatment to contain COVID-19 pandemic. The present research aims at investigating the therapeutic potential of Chloroquine and its potent derivative Hydroxychloroquine against SARS-CoV-2 viral proteins. At the same time we have screened some chemically synthesized derivatives of Chloroquine and compared their binding efficacy with chemically synthesized Chloroquine derivatives through <i>in silico</i>approaches. For the purpose of the study, we have selected some essential viral proteins and enzymes implicated in SARS-CoV-2 replication and multiplication as putative drug targets.<br>

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Curcumin Nanoparticles as Promising Therapeutic Agents for Drug Targets

Molecules ◽

10.3390/molecules26164998 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4998

Author(s):

Hitesh Chopra ◽

Protity Shuvra Dey ◽

Debashrita Das ◽

Tanima Bhattacharya ◽

Muddaser Shah ◽

...

Keyword(s):

Drug Targets ◽

Therapeutic Potential ◽

Curcuma Longa ◽

Therapeutic Agents ◽

Target Specificity ◽

Production Scale ◽

Curcumin Nanoparticles ◽

Active Moiety ◽

Bioactive Component ◽

Biological Studies

Curcuma longa is very well-known medicinal plant not only in the Asian hemisphere but also known across the globe for its therapeutic and medicinal benefits. The active moiety of Curcuma longa is curcumin and has gained importance in various treatments of various disorders such as antibacterial, antiprotozoal, cancer, obesity, diabetics and wound healing applications. Several techniques had been exploited as reported by researchers for increasing the therapeutic potential and its pharmacological activity. Here, the dictum is the new room for the development of physicochemical, as well as biological, studies for the efficacy in target specificity. Here, we discussed nanoformulation techniques, which lend support to upgrade the characters to the curcumin such as enhancing bioavailability, increasing solubility, modifying metabolisms, and target specificity, prolonged circulation, enhanced permeation. Our manuscript tried to seek the attention of the researcher by framing some solutions of some existing troubleshoots of this bioactive component for enhanced applications and making the formulations feasible at an industrial production scale. This manuscript focuses on recent inventions as well, which can further be implemented at the community level.

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Long Noncoding RNA: Regulatory Mechanisms and Therapeutic Potential in Sepsis

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.563126 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Wang ◽

Ni Yang ◽

Ri Wen ◽

Chun-Feng Liu ◽

Tie-Ning Zhang

Keyword(s):

Host Response ◽

Noncoding Rna ◽

Therapeutic Potential ◽

Noncoding Rnas ◽

Specific Treatment ◽

Kidney Injury ◽

Biological Processes ◽

Immune Functions ◽

Life Threatening ◽

Organ Dysfunctions

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is characterized by a hyperinflammatory state accompanied by immunosuppression. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 nucleotides and have important roles in mediating various biological processes. Recently, lncRNAs were found to exert both promotive and inhibitory immune functions in sepsis, thus participating in sepsis regulation. Additionally, several studies have revealed that lncRNAs are involved in sepsis-induced organ dysfunctions, including cardiovascular dysfunction, acute lung injury, and acute kidney injury. Considering the lack of effective biomarkers for early identification and specific treatment for sepsis, lncRNAs may be promising biomarkers and even targets for sepsis therapies. This review systematically highlights the recent advances regarding the roles of lncRNAs in sepsis and sheds light on their use as potential biomarkers and treatment targets for sepsis.

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A new genetic method to predict the prognostic outcome of melanoma

10.1101/2020.03.09.984732 ◽

2020 ◽

Author(s):

Hong GuoHu ◽

Guan Qing ◽

Luo XinHua

Keyword(s):

Regression Analysis ◽

Risk Score ◽

Genetic Risk ◽

Cox Regression ◽

Genetic Risk Score ◽

Biological Processes ◽

Statistical Regression ◽

Cox Regression Analysis ◽

Genetic Method ◽

Prognostic Outcome

AbstractCutaneous melanoma is quite often encountered in dermato-oncology. This paper describes a new genetic method to predict the prognostic outcome of melanoma. Data were collected from the TCGA databases. According to tumor progression status, the data were divided into two groups to evaluate the significant biological processes and key genes influencing the outcome of melanoma using a bioinformatics method. By adopting a statistical regression analysis method, a novel score based on the contributing genes was developed. Cox regression analysis was used to validate the effectiveness of the genetic risk score in predicting the outcome. Seven biological processes associated with melanocytes were identified. A protein-protein interactions network showed that 27 functional genes were associated with the outcome of melanoma. Among these, three genes (COL17A1, ITGA6, and SPRR2F) were used to calculate the genetic risk score, which was regarded as an independent and effective risk factor for disease progression or overall survival in melanoma.

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Sphingosine 1-phosphate in inflammation

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v4i6.1610 ◽

2020 ◽

Vol 4 (6) ◽

Author(s):

Lijuan Li ◽

Lixia An ◽

Lifang Li ◽

Yongjuan Zhao

Keyword(s):

Plasma Membrane ◽

Drug Targets ◽

Therapeutic Potential ◽

Cell Types ◽

In Vivo Models ◽

Integral Role ◽

Sphingosine 1 Phosphate ◽

And Migration

Sphingolipids are formed via the metabolism of sphingomyelin, aconstituent of the plasma membrane, or by denovosynthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in in?ammation. This can involve, for example, activation of pro-in?ammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-in?ammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-af?nity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on in?ammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in in?ammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and in?ammatory bowel disease, which involve important in?ammatory components. A signi?cant body of research now indicates that sphingolipids are intimately involved in the in?ammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological in?ammation.

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Haploinsufficiency of the psychiatric risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

10.1101/417832 ◽

2018 ◽

Cited By ~ 2

Author(s):

Niels Haan ◽

Laura J Westacott ◽

Jenny Carter ◽

Michael J Owen ◽

William P Gray ◽

...

Keyword(s):

Genetic Risk ◽

Hippocampal Neurons ◽

Hippocampal Neurogenesis ◽

Actin Dynamics ◽

Biological Processes ◽

Risk Gene ◽

A Cell ◽

Adult Born Neurons ◽

Newborn Neurons ◽

And Migration

AbstractGenetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons due to reduced apoptosis, without altering proliferation. We confirm this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

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