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Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.

ABSTRACT: Cilia are dynamic microtubule-based organelles present on the surface of many eukaryotic cell types and can be motile or non-motile primary cilia. Cilia defects underlie a growing list of human disorders, collectively called ciliopathies, with overlapping phenotypes such as developmental delays and cognitive and memory deficits. Consistent with this, cilia play an important role in brain development, particularly in neurogenesis and neuronal migration. These findings suggest that a deeper systems-level understanding of how ciliary proteins function together may provide new mechanistic insights into the molecular etiologies of nervous system defects. Towards this end, we performed a protein-protein interaction (PPI) network analysis of known intraflagellar transport, BBSome, transition zone, ciliary membrane and motile cilia proteins. Known PPIs of ciliary proteins were assembled from online databases. Novel PPIs were predicted for each ciliary protein using a computational method we developed, called High-precision PPI Prediction (HiPPIP) model. The resulting cilia "interactome" consists of 165 ciliary proteins, 1,011 known PPIs, and 765 novel PPIs. The cilia interactome revealed interconnections between ciliary proteins, and their relation to several pathways related to neuropsychiatric processes, and to drug targets. Approximately 184 genes in the cilia interactome are targeted by 548 currently approved drugs, of which 103 are used to treat various diseases of nervous system origin. Taken together, the cilia interactome presented here provides novel insights into the relationship between ciliary protein dysfunction and neuropsychiatric disorders, for e.g. interconnections of Alzheimer's disease, aging and cilia genes. These results provide the framework for the rational design of new therapeutic agents for treatment of ciliopathies and neuropsychiatric disorders.

SUBMITTER: Karunakaran KB

PROVIDER: S-EPMC7515907 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.

Karunakaran Kalyani B KB Chaparala Srilakshmi S Lo Cecilia W CW Ganapathiraju Madhavi K MK

Scientific reports 20200924 1

Cilia are dynamic microtubule-based organelles present on the surface of many eukaryotic cell types and can be motile or non-motile primary cilia. Cilia defects underlie a growing list of human disorders, collectively called ciliopathies, with overlapping phenotypes such as developmental delays and cognitive and memory deficits. Consistent with this, cilia play an important role in brain development, particularly in neurogenesis and neuronal migration. These findings suggest that a deeper system ...[more]

PMID: 32973177

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Project description:BackgroundProtein-protein interactions play a fundamental role in elucidating the molecular mechanisms of biomolecular function, signal transductions and metabolic pathways of living organisms. Although high-throughput technologies such as yeast two-hybrid system and affinity purification followed by mass spectrometry are widely used in model organisms, the progress of protein-protein interactions detection in plants is rather slow. With this motivation, our work presents a computational approach to predict protein-protein interactions in Oryza sativa.ResultsTo better understand the interactions of proteins in Oryza sativa, we have developed PRIN, a Predicted Rice Interactome Network. Protein-protein interaction data of PRIN are based on the interologs of six model organisms where large-scale protein-protein interaction experiments have been applied: yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster), human (Homo sapiens), Escherichia coli K12 and Arabidopsis thaliana. With certain quality controls, altogether we obtained 76,585 non-redundant rice protein interaction pairs among 5,049 rice proteins. Further analysis showed that the topology properties of predicted rice protein interaction network are more similar to yeast than to the other 5 organisms. This may not be surprising as the interologs based on yeast contribute nearly 74% of total interactions. In addition, GO annotation, subcellular localization information and gene expression data are also mapped to our network for validation. Finally, a user-friendly web interface was developed to offer convenient database search and network visualization.ConclusionsPRIN is the first well annotated protein interaction database for the important model plant Oryza sativa. It has greatly extended the current available protein-protein interaction data of rice with a computational approach, which will certainly provide further insights into rice functional genomics and systems biology. PRIN is available online at http://bis.zju.edu.cn/prin/.

Project description:Malignant pleural mesothelioma (MPM) is an aggressive cancer affecting the outer lining of the lung, with a median survival of less than one year. We constructed an 'MPM interactome' with over 300 computationally predicted protein-protein interactions (PPIs) and over 2400 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from Biological General Repository for Interaction Datasets (BioGRID) and Human Protein Reference Database (HPRD). Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, and gene expression in microarray experiments, and classifies the pairwise features as interacting or non-interacting based on a random forest model. We validated five novel predicted PPIs experimentally. The interactome is significantly enriched with genes differentially ex-pressed in MPM tumors compared with normal pleura and with other thoracic tumors, genes whose high expression has been correlated with unfavorable prognosis in lung cancer, genes differentially expressed on crocidolite exposure, and exosome-derived proteins identified from malignant mesothelioma cell lines. 28 of the interactors of MPM proteins are targets of 147 U.S. Food and Drug Administration (FDA)-approved drugs. By comparing disease-associated versus drug-induced differential expression profiles, we identified five potentially repurposable drugs, namely cabazitaxel, primaquine, pyrimethamine, trimethoprim and gliclazide. Preclinical studies may be con-ducted in vitro to validate these computational results. Interactome analysis of disease-associated genes is a powerful approach with high translational impact. It shows how MPM-associated genes identified by various high throughput studies are functionally linked, leading to clinically translatable results such as repurposed drugs. The PPIs are made available on a webserver with interactive user interface, visualization and advanced search capabilities.

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Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.

Publications

Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.

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