Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles

2021 ◽  
pp. jmedgenet-2021-108193
Author(s):  
Ido Shalev ◽  
Judith Somekh ◽  
Alal Eran
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Expression Patterns ◽  
Population Variation ◽  
Functional Enrichment ◽  
Phylogenetic Profiling ◽  
Developing Neurons

BackgroundLoss of tectonin β-propeller repeat-containing 2 (TECPR2) function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding TECPR2 function is essential for developing much needed precision therapeutics for TECPR2-related diseases.MethodsWe leveraged considerable amounts of functional data to obtain a comprehensive perspective of the role of TECPR2 in health and disease. We integrated expression patterns, population variation, phylogenetic profiling, protein-protein interactions and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to TECPR2 via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2.ResultsTECPR2 was found to be part of a tight neurodevelopmental gene expression programme that includes KIF1A, ATXN1, TOM1L2 and FA2H, all implicated in neurological diseases. Functional enrichment analyses of TECPR2-related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is non-redundant.ConclusionsTECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer’s disease and Huntington’s disease. Specifically, we speculate that TECPR2 plays an important role as a proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders.

Integrative functional analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles

2020 ◽  
Author(s):  
Ido Shalev ◽  
Judith Somekh ◽  
Alal Eran
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Expression Patterns ◽  
Population Variation ◽  
Functional Enrichment ◽  
Phylogenetic Profiling ◽  
Developing Neurons

Abstract BackgroundLoss of tectonin β-propeller repeat-containing 2 (TECPR2) function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding TECPR2 function is essential for developing much needed precision therapeutics for TECPR2-related diseases. MethodsWe leveraged the considerable amounts of functional data to obtain a comprehensive perspective of the role of TECPR2 in health and disease. We integrated expression patterns, population variation, phylogenetic profiling, protein-protein interactions, and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to TECPR2 via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2.ResultsTECPR2 was found to be part of a tight neurodevelopmental gene expression program that includes KIF1A, ATXN1, TOM1L2, and FA2H, all implicated in neurological diseases. Functional enrichment analyses of TECPR2-related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is nonredundant. ConclusionsTECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer’s disease, Huntington’s disease, and various cancers. Our work further suggests that TECPR2 plays a role as a synaptic proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders.

scholarly journals Role of Enzymes in Causing Neurological Disorders

2021 ◽  
Vol 12 (1) ◽  
pp. 466-476
Author(s):  
Vysakh Visweswaran ◽  
Roshni PR
Keyword(s):  
Neurological Disorders ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Direct Result ◽  
Permanent Disability ◽  
Genetic Abnormalities ◽  
Underlying Pathology

Diseases of the nervous system are always associated with poor prognosis and limited treatment options. The fragile nature of the neurons and their inability to replicate means that neurological disorders are associated with a permanent disability. Pharmacotherapy of neurological diseases requires understanding the molecular mechanisms involved in the disease pathology. In most of the cases a faulty cellular biochemical pathway is involved, resulting from a defective enzyme. This article focusses on role of enzymes in various neurological disorders. To review pertinent literature and summarise the role of enzymes in the underlying pathology of various neurological disorders. A comprehensive literature search was conducted using PubMed, SCOPUS, J-GATE and Google Scholar and relevant papers were collected using the keywords enzymes, Alzheimer's disease, redox, thiamine, depression, neurotransmitters, epileptogenesis. The literature review highlighted the role of enzymes in major neurological disorders and their potential to be used as drug targets and biomarkers. Identifying defective enzymes gives us new molecular targets to focus on for developing more effective pharmacotherapeutic options. They can be also considered as potential biomarkers. An abnormal enzyme is most often a direct result of an underlying genetic abnormality. Identifying and screening for these genetic abnormalities can be used in early identification and prevention of disease in individuals who have a genetic predisposition. The modern advances in genetic engineering shows a lot of promise in correcting these abnormalities and development of revolutionary cures although ethical concerns remain. 

scholarly journals Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ettore Tiraboschi ◽  
Ramon Guirado ◽  
Dario Greco ◽  
Petri Auvinen ◽  
Jose Fernando Maya-Vetencourt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Visual Cortex ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Monocular Deprivation ◽  
Adult Brain ◽  
Gene Expression Patterns ◽  
Postnatal Life ◽  
Critical Periods

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

scholarly journals Molecular signatures of cognition and affect

2020 ◽  
Author(s):  
Justine Y. Hansen ◽  
Ross D. Markello ◽  
Jacob W. Vogel ◽  
Jakob Seidlitz ◽  
Danilo Bzdok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Hierarchical Organization ◽  
Brain Atlas ◽  
Psychological Processes ◽  
Cognitive Architectures ◽  
Neuronal Populations

Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here we directly bridge the microscale and macroscale by mapping gene expression patterns to functional activation patterns across the cortical sheet. Applying unsupervised learning to the Allen Human Brain Atlas and Neurosynth databases, we identify a ventromedial-dorsolateral gradient of gene assemblies that separate affective and cognitive domains. This topographic molecular-psychological signature reflects the hierarchical organization of the neocortex, including systematic variations in cell type, myeloarchitecture, laminar differentiation, and intrinsic network affiliation. In addition, this molecular-psychological signature is related to individual differences in cognitive performance, strengthens over neurodevelopment, and can be replicated in two independent repositories. Collectively, our results reveal spatially covarying transcriptomic and cognitive architectures, highlighting the influence that molecular mechanisms exert on psychological processes.

scholarly journals Transcriptome analysis identifies genes involved in the somatic embryogenesis of Eucalyptus

2020 ◽  
Author(s):  
Yufei Xiao ◽  
Junji Li ◽  
Ye Zhang ◽  
Xiaoning Zhang ◽  
Hailong Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Somatic Embryogenesis ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Expression Patterns ◽  
Late Embryogenesis Abundant ◽  
Arabinogalactan Protein ◽  
Late Embryogenesis Abundant Protein ◽  
Eucalyptus Species

Abstract Background: Eucalyptus, a highly diverse genus of the Myrtaceae family, is the most widely planted hardwood in the world due to its increasing importance for fiber and energy. Somatic embryogenesis (SE) is one large-scale method to provide commercial use of the vegetative propagation of Eucalyptus and dedifferentiation is a key step for plant cells to become meristematic. However, little is known about the molecular changes during the Eucalyptus SE.Results: We compared the transcriptome profiles of the differentiated and dedifferentiated tissues of two Eucalyptus species – E. camaldulensis (high embryogenetic potential) and E. grandis x urophylla (low embryogenetic potential). Initially, we identified 18,777 to 20,240 genes in all samples. Compared to the differentiated tissues, we identified 9,229 and 8,989 differentially expressed genes (DEGs) in the dedifferentiated tissues of E. camaldulensis and E. grandis x urophylla, respectively, and 2,687 up-regulated and 2,581 down-regulated genes shared. Next, we identified 2,003 up-regulated and 1,958 down-regulated genes only in E. camaldulensis, including 6 somatic embryogenesis receptor kinase, 17 ethylene, 12 auxin, 83 ribosomal protein, 28 zinc finger protein, 10 heat shock protein, 9 histone, 122 cell wall related and 98 transcription factor genes. Genes from other families like ABA, arabinogalactan protein and late embryogenesis abundant protein were also found to be specifically dysregulated in the dedifferentiation process of E. camaldulensis. Further, we identified 48,447 variants (SNPs and small indels) specific to E. camaldulensis, including 13,434 exonic variants from 4,723 genes (e.g., annexin, GN, ARF and AP2-like ethylene-responsive transcription factor). qRT-PCR was used to confirm the gene expression patterns in both E. camaldulensis and E. grandis x urophylla. Conclusions: This is the first time to study the somatic embryogenesis of Eucalyptus using transcriptome sequencing. It will improve our understanding of the molecular mechanisms of somatic embryogenesis and dedifferentiation in Eucalyptus. Our results provide a valuable resource for future studies in the field of Eucalyptus and will benefit the Eucalyptus breeding program.

scholarly journals Genetic control of age-related gene expression and complex traits in the human brain

2017 ◽  
Author(s):  
Trevor Martin ◽  
Hunter B. Fraser
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Genetic Variants ◽  
Complex Traits ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Expression Patterns ◽  
Related Gene ◽  
Age Related

AbstractAge is the primary risk factor for many of the most common human diseases—particularly neurodegenerative diseases—yet we currently have a very limited understanding of how each individual’s genome affects the aging process. Here we introduce a method to map genetic variants associated with age-related gene expression patterns, which we call temporal expression quantitative trait loci (teQTL). We found that these loci are markedly enriched in the human brain and are associated with neurodegenerative diseases such as Alzheimer’s disease and Creutzfeldt-Jakob disease. Examining potential molecular mechanisms, we found that age-related changes in DNA methylation can explain some cis-acting teQTLs, and that trans-acting teQTLs can be mediated by microRNAs. Our results suggest that genetic variants modifying age-related patterns of gene expression, acting through both cis- and trans-acting molecular mechanisms, could play a role in the pathogenesis of diverse neurological diseases.

scholarly journals Cellular-resolution gene expression profiling in the neonatal marmoset brain reveals dynamic species- and region-specific differences

2021 ◽  
Vol 118 (18) ◽  
pp. e2020125118
Author(s):  
Yoshiaki Kita ◽  
Hirozumi Nishibe ◽  
Yan Wang ◽  
Tsutomu Hashikawa ◽  
Satomi S. Kikuchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Neural Circuit ◽  
Expression Patterns ◽  
Three Dimensional ◽  
Control Of Gene Expression ◽  
Cellular Resolution

Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)–based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.

scholarly journals Transcriptome analysis identifies genes involved in the somatic embryogenesis of Eucalyptus

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yufei Xiao ◽  
Junji Li ◽  
Ye Zhang ◽  
Xiaoning Zhang ◽  
Hailong Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Somatic Embryogenesis ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Expression Patterns ◽  
Late Embryogenesis Abundant ◽  
Arabinogalactan Protein ◽  
Late Embryogenesis Abundant Protein ◽  
Eucalyptus Species

Abstract Background Eucalyptus, a highly diverse genus of the Myrtaceae family, is the most widely planted hardwood in the world due to its increasing importance for fiber and energy. Somatic embryogenesis (SE) is one large-scale method to provide commercial use of the vegetative propagation of Eucalyptus and dedifferentiation is a key step for plant cells to become meristematic. However, little is known about the molecular changes during the Eucalyptus SE. Results We compared the transcriptome profiles of the differentiated and dedifferentiated tissues of two Eucalyptus species – E. camaldulensis (high embryogenetic potential) and E. grandis x urophylla (low embryogenetic potential). Initially, we identified 18,777 to 20,240 genes in all samples. Compared to the differentiated tissues, we identified 9229 and 8989 differentially expressed genes (DEGs) in the dedifferentiated tissues of E. camaldulensis and E. grandis x urophylla, respectively, and 2687 up-regulated and 2581 down-regulated genes shared. Next, we identified 2003 up-regulated and 1958 down-regulated genes only in E. camaldulensis, including 6 somatic embryogenesis receptor kinase, 17 ethylene, 12 auxin, 83 ribosomal protein, 28 zinc finger protein, 10 heat shock protein, 9 histone, 122 cell wall related and 98 transcription factor genes. Genes from other families like ABA, arabinogalactan protein and late embryogenesis abundant protein were also found to be specifically dysregulated in the dedifferentiation process of E. camaldulensis. Further, we identified 48,447 variants (SNPs and small indels) specific to E. camaldulensis, including 13,434 exonic variants from 4723 genes (e.g., annexin, GN, ARF and AP2-like ethylene-responsive transcription factor). qRT-PCR was used to confirm the gene expression patterns in both E. camaldulensis and E. grandis x urophylla. Conclusions This is the first time to study the somatic embryogenesis of Eucalyptus using transcriptome sequencing. It will improve our understanding of the molecular mechanisms of somatic embryogenesis and dedifferentiation in Eucalyptus. Our results provide a valuable resource for future studies in the field of Eucalyptus and will benefit the Eucalyptus breeding program.

scholarly journals Mitochondrial function, fatty acid metabolism, and immune system are relevant features of pig adipose tissue development

2012 ◽  
Vol 44 (22) ◽  
pp. 1116-1124 ◽  
Author(s):  
Annie Vincent ◽  
Isabelle Louveau ◽  
Florence Gondret ◽  
Bénédicte Lebret ◽  
Marie Damon
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Low Grade ◽  
Large White ◽  
Mitochondrial Energy Metabolism

The molecular mechanisms underlying the genetic control of fat development in humans and livestock species still require characterization. To gain insights on gene expression patterns associated with genetic propensity for adiposity, we compared subcutaneous adipose tissue (SCAT) transcriptomics profiles from two contrasted pig breeds for body fatness. Samples were obtained from Large White (LW; lean phenotype) and Basque pigs (B; low growth and high fat content) at 35 kg ( n = 5 per breed) or 145 kg body weight ( n = 10 per breed). Using a custom adipose tissue microarray, we found 271 genes to be differentially expressed between the two breeds at both stages, out of which 123 were highly expressed in LW pigs and 148 genes were highly expressed in B pigs. Functional enrichment analysis based on gene ontology (GO) terms highlighted gene groups corresponding to the mitochondrial energy metabolism in LW pigs, whereas immune response was found significantly enriched in B pigs. Genes associated with lipid metabolism, such as ELOVL6, a gene involved in fatty acid elongation, had a lower expression in B compared with LW pigs. Furthermore, despite enlarged adipocyte diameters and higher plasma leptin concentration, B pigs displayed reduced lipogenic enzyme activities compared with LW pigs at 145 kg. Altogether, our results suggest that the development of adiposity was associated with a progressive worsening of the metabolic status, leading to a low-grade inflammatory state, and may thus be of significant interest for both livestock production and human health.

scholarly journals Transcriptomic Analysis Provides Novel Insights into Heat Stress Responses in Sheep

Animals ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 387 ◽  
Author(s):  
Zengkui Lu ◽  
Mingxing Chu ◽  
Qing Li ◽  
Meilin Jin ◽  
Xiaojuan Fei ◽  
...  
Keyword(s):  
Heat Stress ◽  
Differentially Expressed Genes ◽  
Stress Responses ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Transcriptomic Analysis ◽  
Differentially Expressed ◽  
P Value ◽  
Comprehensive Overview

With the intensified and large-scale development of sheep husbandry and global warming, sheep heat stress has become an increasingly important issue. However, little is known about the molecular mechanisms related to sheep responses to heat stress. In this study, transcriptomic analysis of liver tissues of sheep in the presence and absence of heat stress was conducted, with the goal of identifying genes and pathways related to regulation when under such stress. After a comparison with the sheep reference genome, 440,226,436 clean reads were obtained from eight libraries. A p-value ≤ 0.05 and fold change ≥ 2 were taken as thresholds for categorizing differentially expressed genes, of which 1137 were identified. The accuracy and reliability of the RNA-Seq results were confirmed by qRT-PCR. The identified differentially expressed genes were significantly associated with 419 GO terms and 51 KEGG pathways, which suggested their participation in biological processes such as response to stress, immunoreaction, and fat metabolism. This study’s results provide a comprehensive overview of sheep heat stress-induced transcriptional expression patterns, laying a foundation for further analysis of the molecular mechanisms of sheep heat stress.

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