scholarly journals Proteomic differences in the hippocampus and cortex of epilepsy brain tissue

2021 ◽  
Author(s):  
Geoffrey Pires ◽  
Dominique Leitner ◽  
Eleanor Drummond ◽  
Evgeny Kanshin ◽  
Shruti Nayak ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Frontal Cortex ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
High Rate ◽  
Label Free ◽  
Protein Subunit ◽  
Unexpected Death ◽  
And Control

Abstract Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with seizures in epilepsy with a broad range of etiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various etiologies, which may allow for novel targeted therapeutic strategies.

scholarly journals Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

2020 ◽  
Author(s):  
Geoffrey Pires ◽  
Dominique Leitner ◽  
Eleanor Drummond ◽  
Evgeny Kanshin ◽  
Shruti Nayak ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Frontal Cortex ◽  
G Protein ◽  
Molecular Mechanisms ◽  
High Rate ◽  
Label Free ◽  
Protein Subunit ◽  
Unexpected Death ◽  
Hippocampal Ca1 ◽  
And Control

AbstractEpilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals Neuropathology in the North American sudden unexpected death in epilepsy registry

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Dominique F Leitner ◽  
Arline Faustin ◽  
Chloe Verducci ◽  
Daniel Friedman ◽  
Christopher William ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
North American ◽  
Focal Cortical Dysplasia ◽  
Brain Activity ◽  
Brain Regions ◽  
Sudden Unexpected Death ◽  
Age At Death ◽  
Unexpected Death ◽  
Whole Brain ◽  
The North

Abstract Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

2020 ◽  
Author(s):  
Nicholas F. Page ◽  
Michael Gandal ◽  
Myka Estes ◽  
Scott Cameron ◽  
Jessie Buth ◽  
...  
Keyword(s):  
Immune Activation ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Repetitive Behaviors ◽  
Anterior Cingulate ◽  
Psychiatric Disease ◽  
Primate Model ◽  
Maternal Immune Activation ◽  
Transcriptomic Changes ◽  
And Control

AbstractBackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection.MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring—an age comparable to mid adolescence in humans.ResultsWe identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes—PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring.ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims

1994 ◽  
Vol 633 (1-2) ◽  
pp. 297-304 ◽  
Author(s):  
Richard F. Cowburn ◽  
Jan O. Marcusson ◽  
Anders Eriksson ◽  
Birgitta Wiehager ◽  
Cora O'Neill
Keyword(s):  
Frontal Cortex ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity ◽  
Protein Subunit

scholarly journals Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression

2021 ◽  
Vol 22 (3) ◽  
pp. 1148 ◽  
Author(s):  
Dawid Szczepankiewicz ◽  
Piotr Celichowski ◽  
Paweł A. Kołodziejski ◽  
Ewa Pruszyńska-Oszmałek ◽  
Maciej Sassek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontal Cortex ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Molecular Mechanisms ◽  
Forced Swim Test ◽  
Lithium Treatment ◽  
Brain Regions ◽  
Non Coding Rnas ◽  
Depressive Episodes

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.

scholarly journals Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

2020 ◽  
Author(s):  
Dominique F. Leitner ◽  
James D. Mills ◽  
Geoffrey Pires ◽  
Arline Faustin ◽  
Eleanor Drummond ◽  
...  
Keyword(s):  
High Risk ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Brain Activity ◽  
Brain Regions ◽  
Sudden Unexpected Death ◽  
Differentially Expressed ◽  
Unexpected Death ◽  
Protein Coding ◽  
The Brain

AbstractSudden unexpected death in epilepsy (SUDEP) is the leading type of epilepsy-related death. Severely depressed brain activity in these cases may impair respiration, arousal, and protective reflexes, occurring as a prolonged postictal generalized EEG suppression (PGES) and resulting in a high-risk for SUDEP. In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and epilepsy cases, contrasting our previously reported robust differences between epilepsy and controls. Transcriptomics in hippocampus and cortex from surgical epilepsy cases segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. Overall, the SUDEP proteome and high-risk SUDEP transcriptome largely reflected other epilepsy cases in the brain regions analyzed, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Thus, studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

scholarly journals Proteomic Analysis of Aqueous Humor Proteins in Association with Cataract Risks: Diabetes and Smoking

2021 ◽  
Vol 10 (24) ◽  
pp. 5731
Author(s):  
Wei-Cheng Chang ◽  
Cho-Hao Lee ◽  
Shih-Hwa Chiou ◽  
Chen-Chung Liao ◽  
Chao-Wen Cheng
Keyword(s):  
Risk Factors ◽  
Aqueous Humor ◽  
High Performance ◽  
Molecular Mechanisms ◽  
Risk Exposure ◽  
Label Free ◽  
Patients With Diabetes ◽  
Liquid Chromatography Tandem Mass ◽  
And Control ◽  
Control Samples

Cataracts are one of the most common eye diseases that can cause blindness. Discovering susceptibility factors in the proteome that contribute to cataract development would be helpful in gaining new insights in the molecular mechanisms of the cataract process. We used label-free nanoflow ultra-high-performance liquid chromatography–tandem mass spectrometry to compare aqueous humor protein expressions in cataract patients with different cataract risk factors such as diabetes mellitus (DM) and smoking and in controls (with cataract) without risk exposure. Eight patients with diabetes and who smoked (with double risk factors), five patients with diabetes and five patients who smoked (both with a single risk factor), and nine aged-matched cataract controls patients (non-risk exposure) were enrolled. In total, 136 aqueous humor proteins were identified, of which only alpha-2-Heremans–Schmid (HS)-glycoprotein was considered to be significantly risk-associated because it was differentially expressed in these three groups and exhibited increased expression with increasing risk factors. Significant changes in the aqueous humor level of alpha-2-HS-glycoprotein between DM and control samples and between smoking and control samples were confirmed using ELISA. The alpha-2-HS-glycoprotein, called fetuin-a, could be a potential aqueous biomarker associated with DM and smoking, which were cataract risk factors.

scholarly journals Proteomics and Transcriptomics of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Patients

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011999
Author(s):  
Dominique F. Leitner ◽  
James D. Mills ◽  
Geoffrey Pires ◽  
Arline Faustin ◽  
Eleanor Drummond ◽  
...  
Keyword(s):  
High Risk ◽  
Frontal Cortex ◽  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Brain Activity ◽  
Temporal Cortex ◽  
Mesial Temporal Lobe Epilepsy ◽  
Molecular Signaling ◽  
Unexpected Death ◽  
Protein Coding

Objective:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients.Methods:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes.Results:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus.Conclusion:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP

scholarly journals Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 683
Author(s):  
Zdenka Drastichova ◽  
Lucie Hejnova ◽  
Radka Moravcova ◽  
Jiri Novotny
Keyword(s):  
Synaptic Plasticity ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Morphine Withdrawal ◽  
Synaptic Proteins ◽  
Label Free ◽  
Presynaptic Nerve Terminal ◽  
Cytoskeleton Organization ◽  
Associated Proteins

Drug withdrawal is associated with abstinence symptoms including deficits in cognitive functions that may persist even after prolonged discontinuation of drug intake. Cognitive deficits are, at least partially, caused by alterations in synaptic plasticity but the precise molecular mechanisms have not yet been fully identified. In the present study, changes in proteomic and phosphoproteomic profiles of selected brain regions (cortex, hippocampus, striatum, and cerebellum) from rats abstaining for six months after cessation of chronic treatment with morphine were determined by label-free quantitative (LFQ) proteomic analysis. Interestingly, prolonged morphine withdrawal was found to be associated especially with alterations in protein phosphorylation and to a lesser extent in protein expression. Gene ontology (GO) term analysis revealed enrichment in biological processes related to synaptic plasticity, cytoskeleton organization, and GTPase activity. More specifically, significant changes were observed in proteins localized in synaptic vesicles (e.g., synapsin-1, SV2a, Rab3a), in the active zone of the presynaptic nerve terminal (e.g., Bassoon, Piccolo, Rims1), and in the postsynaptic density (e.g., cadherin 13, catenins, Arhgap35, Shank3, Arhgef7). Other differentially phosphorylated proteins were associated with microtubule dynamics (microtubule-associated proteins, Tppp, collapsin response mediator proteins) and the actin–spectrin network (e.g., spectrins, adducins, band 4.1-like protein 1). Taken together, a six-month morphine withdrawal was manifested by significant alterations in the phosphorylation of synaptic proteins. The altered phosphorylation patterns modulating the function of synaptic proteins may contribute to long-term neuroadaptations induced by drug use and withdrawal.

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