The HLA 8.1 ancestral haplotype in schizophrenia: dual implication in neuro‐synaptic pruning and autoimmunity?

2020 ◽  
Vol 141 (2) ◽  
pp. 169-171 ◽  
Author(s):  
R. Tamouza ◽  
R. Krishnamoorthy ◽  
I. Giegling ◽  
M. Leboyer ◽  
D. Rujescu
Keyword(s):  
Ancestral Haplotype ◽  
Synaptic Pruning

Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia

Acta Naturae ◽  
2011 ◽  
Vol 3 (3) ◽  
pp. 52-63 ◽  
Author(s):  
L U Dzhemileva ◽  
O L Posukh ◽  
N A Barashkov ◽  
S A Fedorova ◽  
F M Teryutin ◽  
...  
Keyword(s):  
Haplotype Diversity ◽  
Ancestral Haplotype ◽  
35Delg Mutation

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals Neuroinflammation and Brain Development: Possible Risk Factors in COVID-19-Infected Children

2021 ◽  
pp. 1-7
Author(s):  
Luana da Silva Chagas ◽  
Poliana Capucho Sandre ◽  
Patricia Coelho de Velasco ◽  
Henrique Marcondes ◽  
Natalia Cristina Aparecida Ribeiro e Ribeiro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Fatty Acids ◽  
Brain Development ◽  
Neural Development ◽  
Viral Infections ◽  
Additional Risk ◽  
Autoimmune Hypothyroidism ◽  
Inflammatory Syndrome ◽  
Nutritional Imbalance ◽  
Synaptic Pruning

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.

scholarly journals perfectphyloR: An R package for reconstructing perfect phylogenies

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Charith B. Karunarathna ◽  
Jinko Graham
Keyword(s):  
Binary Tree ◽  
Sequence Data ◽  
R Package ◽  
Binary Sequences ◽  
Ancestral Haplotype ◽  
Perfect Phylogeny ◽  
Nested Partitions ◽  
Genetic Sequence ◽  
Insight Into ◽  
Rooted Binary Tree

Abstract Background A perfect phylogeny is a rooted binary tree that recursively partitions sequences. The nested partitions of a perfect phylogeny provide insight into the pattern of ancestry of genetic sequence data. For example, sequences may cluster together in a partition indicating that they arise from a common ancestral haplotype. Results We present an R package to reconstruct the local perfect phylogenies underlying a sample of binary sequences. The package enables users to associate the reconstructed partitions with a user-defined partition. We describe and demonstrate the major functionality of the package. Conclusion The package should be of use to researchers seeking insight into the ancestral structure of their sequence data. The reconstructed partitions have many applications, including the mapping of trait-influencing variants.

scholarly journals The myositis clinical phenotype associated with anti-Zo autoantibodies: a case series of nine UK patients

Rheumatology ◽  
2019 ◽  
Vol 59 (7) ◽  
pp. 1626-1631 ◽  
Author(s):  
Sarah L Tansley ◽  
Zoe Betteridge ◽  
Hui Lu ◽  
Emma Davies ◽  
Simon Rothwell ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Interstitial Pneumonia ◽  
Clinical Phenotype ◽  
Disease Onset ◽  
Usual Interstitial Pneumonia ◽  
Trna Synthetase ◽  
Muscle Disease ◽  
Ancestral Haplotype ◽  
Common Finding

Abstract Objectives It has been over 10 years since the first report of autoantibodies directed against phenylalanyl tRNA synthetase (anti-Zo) in a patient with features of the anti-synthetase syndrome. In that time no further cases have been published. Here we aim to characterize more fully the clinical phenotype of anti-Zo–associated myositis by describing the clinical features of nine patients. Methods Anti-Zo was identified by protein-immunoprecipitation in patients referred for extended spectrum myositis autoantibody testing at our laboratory. Results were confirmed by immunodepletion using a reference serum. Medical records were retrospectively reviewed to provide detailed information of the associated clinical phenotype for all identified patients. Where possible, HLA genotype was imputed using Illumina protocols. Results Nine patients with anti-Zo were identified. The median age at disease onset was 51 years, and six patients were female. Seven patients had evidence of inflammatory muscle disease, seven of interstitial lung disease and six of arthritis. The reported pattern of interstitial lung disease varied with usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia all described. Other features of the anti-synthetase syndrome such as RP and mechanics hands were common. HLA data was available for three patients, all of whom had at least one copy of the HLA 8.1 ancestral haplotype. Conclusion Patients with anti-Zo presenting with features of the anti-synthetase syndrome and interstitial lung disease is a common finding. Like other myositis autoantibodies, there is likely to be a genetic association with the HLA 8.1 ancestral haplotype.

scholarly journals Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Cell ◽  
2016 ◽  
Vol 165 (4) ◽  
pp. 921-935 ◽  
Author(s):  
Hansen Lui ◽  
Jiasheng Zhang ◽  
Stefanie R. Makinson ◽  
Michelle K. Cahill ◽  
Kevin W. Kelley ◽  
...  
Keyword(s):  
Complement Activation ◽  
Synaptic Pruning

scholarly journals Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

2019 ◽  
Author(s):  
Max Lam ◽  
W. David Hill ◽  
Joey W. Trampush ◽  
Jin Yu ◽  
Emma Knowles ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Cognitive Ability ◽  
Genetic Correlation ◽  
Allelic Variation ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Biological Mechanisms ◽  
Genetic Level ◽  
Higher Educational Attainment ◽  
Synaptic Pruning

AbstractLiability to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published GWAS in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“Concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants demonstrating the counterintuitive (“Discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education and/or schizophrenia at p<5×10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs, and many of these have been validated by larger, more recent single-phenotype GWAS. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms: early neurodevelopmental pathways that characterize concordant allelic variation, and adulthood synaptic pruning pathways that were linked to the paradoxical positive genetic association between education and schizophrenia. Further, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia, but also to the broader biological dimensions that are implicated in both general health outcomes and psychiatric illness.

scholarly journals Identification of Neuronal Pentraxins as Synaptic Binding Partners of C1q and the Involvement of NP1 in Synaptic Pruning in Adult Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Réka Á. Kovács ◽  
Henrietta Vadászi ◽  
Éva Bulyáki ◽  
György Török ◽  
Vilmos Tóth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Potential Interaction ◽  
Synaptic Function ◽  
Classical Pathway ◽  
Microglial Phagocytosis ◽  
Classical Complement Pathway ◽  
Adult Mice ◽  
Synaptic Pruning

Elements of the immune system particularly that of innate immunity, play important roles beyond their traditional tasks in host defense, including manifold roles in the nervous system. Complement-mediated synaptic pruning is essential in the developing and healthy functioning brain and becomes aberrant in neurodegenerative disorders. C1q, component of the classical complement pathway, plays a central role in tagging synapses for elimination; however, the underlying molecular mechanisms and interaction partners are mostly unknown. Neuronal pentraxins (NPs) are involved in synapse formation and plasticity, moreover, NP1 contributes to cell death and neurodegeneration under adverse conditions. Here, we investigated the potential interaction between C1q and NPs, and its role in microglial phagocytosis of synapses in adult mice. We verified in vitro that NPs interact with C1q, as well as activate the complement system. Flow cytometry, immunostaining and co-immunoprecipitation showed that synapse-bound C1q colocalizes and interacts with NPs. High-resolution confocal microscopy revealed that microglia-surrounded C1q-tagged synapses are NP1 positive. We have also observed the synaptic occurrence of C4 suggesting that activation of the classical pathway cannot be ruled out in synaptic plasticity in healthy adult animals. In summary, our results indicate that NPs play a regulatory role in the synaptic function of C1q. Whether this role can be intensified upon pathological conditions, such as in Alzheimer’s disease, is to be disclosed.

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