scholarly journals Molecular Basis of GABA Hypofunction in Adolescent Schizophrenia-Like Animals

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Xiaodan Wang ◽  
Ying Hu ◽  
Wenxin Liu ◽  
Yuanyuan Ma ◽  
Xi Chen ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Drug Targets ◽  
Neurodevelopmental Disorder ◽  
Early Adulthood ◽  
Gaba Synthesis ◽  
Neurochemical Changes ◽  
Gaba Transmission ◽  
Related Proteins ◽  
Abnormal Behaviors ◽  
Cell Data

Schizophrenia is a neurodevelopmental disorder that NMDA receptor (NMDAR) hypofunction appears centrally involved. Schizophrenia typically emerges in adolescence or early adulthood. Electrophysiological and several neurochemical changes have linked the GABA deficits to abnormal behaviors induced by NMDAR hypofunction. However, few studies have systematically investigated the molecular basis of GABA deficits, especially during adolescence. To address this issue, we transiently administrated MK-801 to mice on PND 10, which exhibited schizophrenia-relevant deficits in adolescence. Slice recording showed reduced GABA transmission and PVI+ hypofunction, indicating GABAergic hypofunction. Cortical proteomic evaluation combined with analysis of single cell data from the Allen Brain showed that various metabolic processes were enriched in top ranks and differentially altered in excitatory neurons, GABAergic interneurons, and glial cells. Notably, the GABA-related amino acid metabolic process was disturbed in both astrocytes and interneurons, in which we found a downregulated set of GABA-related proteins (GAD65, SYNPR, DBI, GAT3, SN1, and CPT1A). They synergistically regulate GABA synthesis, release, reuptake, and replenishment. Their downregulation indicates impaired GABA cycle and homeostasis regulated by interneuron-astrocyte communication in adolescence. Our findings on molecular basis of GABA deficits could provide potential drug targets of GABAergic rescue for early prevention and intervention.

scholarly journals Molecular basis for chirality-regulated Aβ self-assembly and receptor recognition revealed by ion mobility-mass spectrometry

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Gongyu Li ◽  
Kellen DeLaney ◽  
Lingjun Li
Keyword(s):  
Mass Spectrometry ◽  
Ion Mobility ◽  
Self Assembly ◽  
Molecular Basis ◽  
Drug Targets ◽  
Molecular Evidence ◽  
Ion Mobility Mass Spectrometry ◽  
Epitope Region ◽  
Receptor Recognition ◽  
Chiral Effects

Abstract Despite extensive efforts on probing the mechanism of Alzheimer’s disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets. Herein, we focus on the chiral effects of truncated amyloid beta (Aβ) and offer further structural and molecular evidence for epitope region-specific, chirality-regulated Aβ fragment self-assembly and its potential impact on receptor-recognition. A multidimensional ion mobility-mass spectrometry (IM-MS) analytical platform and in-solution kinetics analysis reveal the comprehensive structural and molecular basis for differential Aβ fragment chiral chemistry, including the differential and cooperative roles of chiral Aβ N-terminal and C-terminal fragments in receptor recognition. Our method is applicable to many other systems and the results may shed light on the potential development of novel AD therapeutic strategies based on targeting the D-isomerized Aβ, rather than natural L-Aβ.

scholarly journals Hrr25 triggers selective autophagy–related pathways by phosphorylating receptor proteins

2014 ◽  
Vol 207 (1) ◽  
pp. 91-105 ◽  
Author(s):  
Chikara Tanaka ◽  
Li-Jing Tan ◽  
Keisuke Mochida ◽  
Hiromi Kirisako ◽  
Michiko Koizumi ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Molecular Basis ◽  
Receptor Proteins ◽  
Selective Autophagy ◽  
The Core ◽  
The Common ◽  
Related Proteins

In selective autophagy, degradation targets are specifically recognized, sequestered by the autophagosome, and transported into the lysosome or vacuole. Previous studies delineated the molecular basis by which the autophagy machinery recognizes those targets, but the regulation of this process is still poorly understood. In this paper, we find that the highly conserved multifunctional kinase Hrr25 regulates two distinct selective autophagy–related pathways in Saccharomyces cerevisiae. Hrr25 is responsible for the phosphorylation of two receptor proteins: Atg19, which recognizes the assembly of vacuolar enzymes in the cytoplasm-to-vacuole targeting pathway, and Atg36, which recognizes superfluous peroxisomes in pexophagy. Hrr25-mediated phosphorylation enhances the interactions of these receptors with the common adaptor Atg11, which recruits the core autophagy-related proteins that mediate the formation of the autophagosomal membrane. Thus, this study introduces regulation of selective autophagy as a new role of Hrr25 and, together with other recent studies, reveals that different selective autophagy–related pathways are regulated by a uniform mechanism: phosphoregulation of the receptor–adaptor interaction.

Autism Spectrum Disorders in Later Life

2018 ◽  
Author(s):  
Ye In (Jane) Hwang ◽  
Kitty-Rose Foley ◽  
Samuel Arnold ◽  
Julian Trollor
Keyword(s):  
Neurodevelopmental Disorder ◽  
Early Adulthood ◽  
Biological Marker ◽  
Later Life ◽  
Well Being ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Childhood And Adolescence ◽  
Physical And Mental Health ◽  
Autistic Adults

Autism spectrum disorder (ASD), or autism, is a neurodevelopmental disorder that is typically recognized and diagnosed in childhood. There is no established biological marker for autism; rather, the diagnosis is made based on observation of behavioral traits, including (a) persistent deficits in social interaction and communication, and (b) restricted, repetitive patterns of behavior, interests, or activities. Because autism is a spectrum disorder, autistic individuals are a highly heterogeneous group and differ widely in the presentation and severity of their symptoms. The established prevalence of ASD is approximately 1% of the population. Information about autism in adulthood is limited; most of the literature examines childhood and adolescence. While the term “later life” has traditionally been associated with those over the age of 65, a dire lack of understanding exists for those on the autism spectrum beyond early adulthood. Individuals remain on the spectrum into later life, though some mild improvements in symptoms are observed over time. Autistic adults experience high levels of physical and mental health comorbidities. Rates of participation in employment and education are also lower than that of the general population. Quality of life is reportedly poorer for autistic adults than for nonautistic peers, though this is not affected by age. More robust studies of the health, well-being, and needs of autistic adults are needed, especially qualitative investigations of adulthood and aging and longitudinal studies of development over the lifespan.

scholarly journals Prion and Prion-Like Protein Strains: Deciphering the Molecular Basis of Heterogeneity in Neurodegeneration

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 261 ◽  
Author(s):  
Carlo Scialò ◽  
Elena De Cecco ◽  
Paolo Manganotti ◽  
Giuseppe Legname
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Amyloid Β ◽  
Dna Binding Protein ◽  
Propagation Process ◽  
Replication Process ◽  
Therapeutic Implications ◽  
Pathological Mechanism ◽  
The Central Nervous System ◽  
Related Proteins

Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of “prion-like” to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.

scholarly journals VTR: an algorithm for identifying analogous contacts on protein structures and their complexes

2020 ◽  
Author(s):  
Vitor Pimentel ◽  
Diego Mariano ◽  
Letícia Xavier Silva Cantão ◽  
Luana Luiza Bastos ◽  
Pedro Fischer ◽  
...  
Keyword(s):  
Case Studies ◽  
Drug Targets ◽  
Rational Design ◽  
Structural Alignment ◽  
Protein Structures ◽  
Cell Receptor ◽  
Industrial Applications ◽  
Biofuel Production ◽  
Homologous Proteins ◽  
Related Proteins

Abstract Evolutionarily related proteins can present similar structures but very dissimilar sequences. Hence, understanding the role of the inter-residues contacts for the protein structure has been the target of many studies. Contacts comprise non-covalent interactions, which are essential to stabilize macromolecular structures such as proteins. Here we show VTR, a new method for the detection of analogous contacts in protein pairs. VTR performs structural alignment between proteins and detects interactions that occur in similar regions. To evaluate our tool, we proposed three case studies: (i) we compared a vertebrate myoglobin and a truncated invertebrate hemoglobin; (ii) analyzed interactions between the spike protein RBD of SARS-CoV-2 and the cell receptor ACE2; and (iii) compared a glucose-tolerant and a non-tolerant β-glucosidase enzyme used for biofuel production. The case studies demonstrate the potential of VTR for the understanding of functional similarities between distantly sequence-related proteins, as well as the exploration of important drug targets and rational design of enzymes for industrial applications. We envision VTR as a promising tool for understanding differences and similarities between homologous proteins with similar 3D structures but different sequences. VTR is available at http://bioinfo.dcc.ufmg.br/vtr.

scholarly journals Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer

2020 ◽  
pp. jbc.RA120.016019
Author(s):  
Mussa Quareshy ◽  
Muralidharan Shanmugam ◽  
Eleanor Townsend ◽  
Eleanor Jameson ◽  
Timothy D.H. Bugg ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Molecular Basis ◽  
Drug Targets ◽  
Structural Basis ◽  
Paramagnetic Resonance ◽  
Group V ◽  
Mononuclear Iron ◽  
Quaternary Ammonium Group ◽  
Accelerate Atherosclerosis ◽  
Rieske Oxygenases

Microbial metabolism of carnitine to trimethylamine (TMA) in the gut can accelerate atherosclerosis and heart disease and these TMA-producing enzymes are therefore important drug targets. Here, we report the first structures of the carnitine oxygenase CntA, an enzyme of the Rieske oxygenase family. CntA exists in a head-to-tail a3 trimeric structure. The two functional domains (the Rieske and the catalytic mononuclear iron domains) are located > 40 Å apart in the same monomer but adjacent in two neighbouring monomers. Structural determination of CntA and subsequent electron paramagnetic resonance measurements uncover the molecular basis of the so-called bridging glutamate (E205) residue in inter-subunit electron transfer. The structures of the substrate-bound CntA help to define the substrate pocket. Importantly, a tyrosine residue (Y203) is essential for ligand recognition through a π-cation interaction with the quaternary ammonium group. This interaction between an aromatic residue and quaternary amine substrates allows us to delineate a subgroup of Rieske oxygenases (group V) from the prototype ring-hydroxylating Rieske oxygenases involved in bioremediation of aromatic pollutants in the environment. Furthermore, we report the discovery of the first known CntA inhibitors and solve the structure of CntA in complex with the inhibitor, demonstrating the pivotal role of Y203 through a π-π stacking interaction with the inhibitor. Our study provides the structural and molecular basis for future discovery of drugs targeting this TMA-producing enzyme in human gut.

scholarly journals VTR: A Web Tool for Identifying Analogous Contacts on Protein Structures and Their Complexes

2021 ◽  
Vol 1 ◽  
Author(s):  
Vitor Pimentel ◽  
Diego Mariano ◽  
Letícia Xavier Silva Cantão ◽  
Luana Luiza Bastos ◽  
Pedro Fischer ◽  
...  
Keyword(s):  
Case Studies ◽  
Drug Targets ◽  
Rational Design ◽  
Structural Alignment ◽  
Protein Structures ◽  
Industrial Applications ◽  
Biofuel Production ◽  
Web Tool ◽  
Homologous Proteins ◽  
Related Proteins

Evolutionarily related proteins can present similar structures but very dissimilar sequences. Hence, understanding the role of the inter-residues contacts for the protein structure has been the target of many studies. Contacts comprise non-covalent interactions, which are essential to stabilize macromolecular structures such as proteins. Here we show VTR, a new method for the detection of analogous contacts in protein pairs. The VTR web tool performs structural alignment between proteins and detects interactions that occur in similar regions. To evaluate our tool, we proposed three case studies: we 1) compared vertebrate myoglobin and truncated invertebrate hemoglobin; 2) analyzed interactions between the spike protein RBD of SARS-CoV-2 and the cell receptor ACE2; and 3) compared a glucose-tolerant and a non-tolerant β-glucosidase enzyme used for biofuel production. The case studies demonstrate the potential of VTR for the understanding of functional similarities between distantly sequence-related proteins, as well as the exploration of important drug targets and rational design of enzymes for industrial applications. We envision VTR as a promising tool for understanding differences and similarities between homologous proteins with similar 3D structures but different sequences. VTR is available at http://bioinfo.dcc.ufmg.br/vtr.

RHEUMATOID ARTHRITIS: ETIOPATHOGENESIS AND MOLECULAR BASIS

2021 ◽  
pp. 4-10
Author(s):  
Eliseo Ruiz Bedolla ◽  
Briceida Lopez Martinez ◽  
Israel Parra Ortega
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Basis ◽  
Drug Targets ◽  
Current Knowledge ◽  
Experimental Models ◽  
Molecular Pathogenesis ◽  
Amino Acid Catabolism ◽  
New Drug

Rheumatoid arthritis (RA) is the most common form of inammatory arthropathy sustained by autoimmune responses. This review has the objective of updating the knowledge about RA especially its molecular pathogenesis. We examine here the current knowledge of tryptophan, arginine, homoarginine and histidine metabolism and the main immunoregulatory pathways in amino acid catabolism in both RA patients and experimental models of arthritis. Of the characteristic autoantibodies of RA, those that appear earlier, are those that recognize cyclic citrullinated peptides. (CCP) and/or citrullinated brinogen. Therefore our analysis would indicate that amino acids metabolism represents a fruitful area of research for new drug targets for a more effective and safe therapy of RA.

scholarly journals Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment

2019 ◽  
Author(s):  
Tor-Arne Hegvik ◽  
Kai Waløen ◽  
Sunil K. Pandey ◽  
Stephen V. Faraone ◽  
Jan Haavik ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Drug Targets ◽  
Neurodevelopmental Disorder ◽  
Hyperactivity Disorder ◽  
Starting Point ◽  
Adhd Treatment ◽  
Gwa Studies ◽  
Druggable Genome ◽  
Morbid Conditions

Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

Brain maturational processes and delayed onset in schizophrenia

1999 ◽  
Vol 11 (3) ◽  
pp. 525-543 ◽  
Author(s):  
MATCHERI S. KESHAVAN ◽  
GERARD E. HOGARTY
Keyword(s):  
Cognitive Deficits ◽  
Social Cognitive ◽  
Neurodevelopmental Disorder ◽  
Early Adulthood ◽  
Cognitive Capacity ◽  
Central Feature ◽  
Research Strategies ◽  
Therapeutic Implications ◽  
Processing Styles ◽  
The Brain

The central feature of schizophrenia is its onset in adolescence. Although this clinical observation is consistent with the view that schizophrenia may be a neurodevelopmental disorder, debate has focused on when the proposed brain maturational deviations may begin and what might be the nature of such defective development. Conflicting models of this illness (e.g., the early and late neurodevelopmental models) have been proposed. In this paper, we will first review concepts from basic developmental neurobiology pertinent to these issues; we then summarize aspects of the neurobiology of schizophrenia that have a particular bearing on the adolescent onset of this illness. We propose that the schizophrenic syndrome may result from early brain adversity and late maturational processes of brain development interacting with adverse humoral, biochemical, and psychosocial factors during adolescence and early adulthood. The onset of schizophrenia in adolescence may be related to the “plasticity switch” secondary to the peripubertal brain maturational changes, perhaps involving an alteration in glutamate receptor function. This loss of plasticity could result in social and nonsocial cognitive deficits that are central to the pathophysiology of schizophrenia; the vulnerable person may therefore utilize prepubertal processing styles that are insufficient to the adaptive and “gistful” abstraction requirements of adult cognition. Schizophrenia onset might occur in the context of psychosocial developmental challenges to a delayed social cognitive capacity among neurodevelopmentally compromised individuals. We review therapeutic implications as well as testable predictions generated by this model, and discuss research strategies that might further our understanding of the brain maturational abnormalities in schizophrenia.

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