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1.
Biol Chem ; 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39425975

RESUMO

The amyloid precursor protein (APP) can be modulated by the binding of copper and zinc ions. Both ions bind with low nanomolar affinities to both subdomains (E1 and E2) in the extracellular domain of APP. However, the impact of ion binding on structural and mechanical trans-dimerization properties is yet unclear. Using a bead aggregation assay (BAA), we found that zinc ions increase the dimerization of both subdomains, while copper promotes only dimerization of the E1 domain. In line with this, scanning force spectroscopy (SFS) analysis revealed an increase in APP adhesion force up to three-fold for copper and zinc. Interestingly, however, copper did not alter the separation length of APP dimers, whereas high zinc concentrations caused alterations in the structural features and a decrease of separation length. Together, our data provide clear differences in copper and zinc mediated APP trans-dimerization and indicate that zinc binding might favor a less flexible APP structure. This fact is of significant interest since changes in zinc and copper ion homeostasis are observed in Alzheimer's disease (AD) and were reported to affect synaptic plasticity. Thus, modulation of APP trans-dimerization by copper and zinc could contribute to early synaptic instability in AD.

2.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674483

RESUMO

'Candidatus Phytoplasma mali' ('Ca. P. mali') has only one major membrane protein, the immunodominant membrane protein (Imp), which is regarded as being close to the ancestor of all phytoplasma immunodominant membrane proteins. Imp binds to actin and possibly facilitates its movement in the plant or insect host cells. However, protein sequences of Imp are quite diverse among phytoplasma species, thus resulting in difficulties in identifying conserved domains across species. In this work, we compare Imp protein sequences of 'Ca. P. mali' strain PM19 (Imp-PM19) with Imp of different strains of 'Ca. P. mali' and identify its actin-binding domain. Moreover, we show that Imp binds to the actin of apple (Malus x domestica), which is the host plant of 'Ca. P. mali'. Using molecular and scanning force spectroscopy analysis, we find that the actin-binding domain of Imp-PM19 contains a highly positively charged amino acid cluster. Our result could allow investigating a possible correlation between Imp variants and the infectivity of the corresponding 'Ca. P. mali' isolates.


Assuntos
Malus , Phytoplasma , Actinas/metabolismo , Mali , Plantas , Proteínas de Membrana/metabolismo , Doenças das Plantas
3.
Eur Arch Psychiatry Clin Neurosci ; 270(2): 169-181, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30929061

RESUMO

Preliminary evidence suggests that BDNF (brain derived neurotrophic factor) rs6265 genetic polymorphism, BDNF gene promotor methylation and BDNF serum levels might play an important role in the pathogenesis of affective disorders. As studies testing the BDNF system across molecular levels are sparse, this study aimed at investigating the BDNF val66met genotype, BDNF DNA methylation changes and peripheral BDNF serum levels in acute and remitted phases of MDD (major depressive disorder) and BD (bipolar disorder) and healthy controls. We found a significant difference of methylation levels at CpG site 1-1-1 and 3-1-1 between MDD and healthy controls (p < 0.003) with MDD patients showing significantly higher methylation levels. CpG 5-2-1 revealed a statistically significant difference between MDD and healthy controls and MDD and BD (p = 0.00003). Similar to the results of the methylation analysis a significant difference between MDD and healthy controls was found in BDNF serum levels (p = 0.002) with significantly lower BDNF serum levels in MDD compared to healthy controls. A difference between the samples from admission and discharge from hospital of both BDNF gene methylation and serum levels could not be detected in the present study and no influence of the BDNF val66met genotype on neither methylation nor BDNF serum level.


Assuntos
Transtorno Bipolar/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Metilação de DNA , Transtorno Depressivo Maior/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/genética , Transtorno Bipolar/terapia , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Alta do Paciente , Regiões Promotoras Genéticas , Indução de Remissão
4.
Compr Psychiatry ; 102: 152196, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927367

RESUMO

INTRODUCTION: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. MATERIALS AND METHODS: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. RESULTS: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). LIMITATIONS: The significance of the results is limited by the retrospective design and methodological aspects. DISCUSSION: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.


Assuntos
Transtorno Depressivo , Interleucina-8 , Quimiocinas , Citocinas , Transtorno Depressivo/diagnóstico , Humanos , Estudos Retrospectivos
5.
Eur Child Adolesc Psychiatry ; 29(5): 691-706, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31422473

RESUMO

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LALA genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.


Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Encéfalo/patologia , Depressão/tratamento farmacológico , Depressão/psicologia , Técnicas de Genotipagem/métodos , Acontecimentos que Mudam a Vida , Imageamento por Ressonância Magnética/métodos , Adolescente , Criança , Feminino , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
6.
Phys Chem Chem Phys ; 21(28): 15833-15844, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282504

RESUMO

Ultrathin films of tetracyanoethylene (TCNE) on Co(100) were investigated by means of spin-integrated and spin-resolved photoemission spectroscopy ((sp-)UPS), X-ray photoemission spectroscopy (XPS), near edge X-ray absorption fine-structure spectroscopy (NEXAFS), and X-ray magnetic circular dichroism (XMCD). We found a coverage-dependent modulation of the interface dipole and a switching between a metallic and a resistive spin filtering at the interface triggered by two distinct adsorption geometries of TCNE. The strongest hybridization and spin structure modifications are found at low coverage with a face-on adsorption geometry indicating changes in the distance between the surface Co atoms beneath. TCNE has the potential to manipulate the magnetic moments in the Co surface itself, including the possibility of magnetic hardening effects. In summary, the system TCNE/Co offers an experimentally rather easy and controllable way to build up a stable molecular platform stabilizing the reactive ferromagnetic Co surface and customizing the electronic and magnetic properties of the resulting spinterface simultaneously. This makes this system very attractive for spintronic applications as an alternative, less reactive but highly spin polarized foundation beside graphene-based systems.

7.
Psychiatr Danub ; 31(2): 249-255, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291233

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is an anxiety disorder caused by highly traumatic experiences. The aim of this study was to investigate the influence of single nucleotide polymorphisms (SNPs) in the neuropeptide S receptor 1 (NPSR1) and the glutamate decarboxylase 1(GAD1) gene on PTSD and its psychopathological aspects among individuals affected by the Balkan wars during the 90s. SUBJECTS AND METHODS: This study was conducted as part of the South Eastern Europe (SEE) study on molecular mechanisms of PTSD. It comprised 719 participants (539 males), including those with current PTSD, remitted PTSD and healthy volunteers. Psychometric evaluation was performed using the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) andthe Brief Symptom Inventory (BSI). We examined NPSR1 single nucleotide polymorphism (SNP) rs324981 and GAD1 variant rs3749034 genotypes. Case-control analyses were carried out using logistical regression to determine genotype differences between all patients that had either current or remitted PTSD and control individuals. To analyse the influence of the analysed SNPs on PTSD severity, we performed linear regression analyses with CAPS and BSI within each of the two patient groups separately. All of the calculations were performed for additive allelic, recessive, dominant and genotypic models. RESULTS: We observed a nominally significant association for the major allele (G) of GAD1 rs3749034 with an increased risk to develop PTSD in a case control analysis in the recessive model (P=0.0315, odds ratio=0.47, SE=0.35). In contrast, a nominally significant association of the minor allele (A) with higher CAPS scores was identified within the patient group with lifetime PTSD in the dominant model (P=0.0372, ß=6.29, SE=2.99). None of these results did withstand correction for multiple tests. No nominal significant results of GAD1 rs3749034 were found with regard to the intensity of psychological BSI symptoms. Case-control analyses of NPSR1 rs324981 revealed a nominally significant higher risk for homozygous T allele carriers to develop PTSD (P=0.0452) in the recessive model. On the other hand, the T allele showed a nominally significant association with higher BSI scores in patients suffering from lifetime PTSD in the recessive model (P=0.0434). Again, these results were not significant anymore after correction for multiple tests. No associations of NPSR1 rs324981 and CAPS score was identified. CONCLUSION: The findings of this study provide some evidence that the NPSR1 and GAD1 polymorphisms might play a role in the development of war-related PTSD and its related psychological expressions. Further research is needed to elucidate the interactions of specific gene variants and environmental factors in the development of PTSD.


Assuntos
Glutamato Descarboxilase/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas G/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Conflitos Armados/psicologia , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Psychiatr Danub ; 31(2): 211-218, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291228

RESUMO

BACKGROUND: The aim of this study is to investigate the association of gene variations of the monoamine oxidase A (MAOA) and the serotonin transporter solute carrier family 6 member 4 (SLC6A4) gene with posttraumatic stress disorder (PTSD) severity and coping strategies in patients with war related PTSD. SUBJECTS AND METHODS: The study included 747 individuals who had experienced war trauma in the South Eastern Europe conflicts between 1991 and 1999. Genotyping of the MAOA VNTR and SLC6A4 tandem repeat polymorphism in combination with rs25531 was done in 719 participants: 232 females and 487 males. Among them, 369 have had current or lifetime PTSD and 350 have had no PTSD symptoms. For psychometric approach we used the Clinician Administrated PTSD Scale (CAPS), the Brief Symptom Inventory (BSI), the adapted Hoffman-Lazarus Coping scale and a basic socio-demographic data questionnaire. RESULTS: There were no significant intergroup (PTSD versus non PTSD) differences in the genotype distribution of MAOA and SLC6A4 gene polymorphisms. The primary finding of our study was that the MAOA short allele (MAOA-S) was nominally significantly associated with the severity of PTSD symptoms in the total subgroup of participants with lifetime PTSD; males for symptoms of hyperarrousal and females with symptoms of re-experience and hyperarousal. In our research the male subsample with current PTSD and MAOA-S genotype had nominally significantly higher scores for some positive coping strategies compared to those carrying the long allele genotype (MAOA-L). There was no significant association between the severity of PTSD symptoms, BSI phenotype, coping scores and the SLC6A4 genotype. CONCLUSION: The present results support the notion that MAOA VNTR gene variation modulates development and recovery of posttraumatic stress disorder in a war traumatised population, but did not support a connection between SLC6A4 gene variations and war related PTSD.


Assuntos
Conflitos Armados/psicologia , Monoaminoxidase/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Psychiatr Danub ; 31(2): 219-226, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291229

RESUMO

BACKGROUND: Exposure to life-threatening events is common and everyone will most likely experience this type of trauma during their lifetime. Reactions to these events are highly heterogeneous and seems to be influenced by genes as well. Some individuals will develop posttraumatic stress disorder (PTSD), while others will not. In this study, our aim was to analyze the correlation between single nucleotide polymorphisms (SNPs) within the oxytocin receptor (OXTR) gene (rs53576 and rs2254298), the RAR-related orphan receptor A (RORA) gene (rs8042149) and the cannabinoid receptor 1 (CNR1) gene (rs1049353) and PTSD. All candidate genes have been previously associated with stress related disorders and the reaction to traumatic events. SUBJECTS AND METHODS: Participants (N=719) have been exposed to war-related trauma during the war in South-Eastern Europe (Bosnia and Herzegovina, Croatia and Kosovo). We correlated the presence and absence of current and lifetime PTSD as well as PTSD severity (Clinician Administered PTSD scale (CAPS)) and current psychopathology (Brief Symptom Inventory (BSI) score) with the mentioned SNPs. DNA was isolated from whole blood and genotyped for OXTR rs2254298 and rs53576 following previously published protocols, for RORA rs8042149 via PCR-RFLP and CNR1 rs1049353 via KASP. RESULTS: Nominally significant results were found for OXTR rs53576 in connection with the CAPS and BSI scores within lifetime PTSD patients. The additive allelic model indicated that G allele carriers achieved lower CAPS (p=0.0090) and BSI (p=0.0408) scores than participants carrying one or two copies of the A allele. These results did not withstand correction for multiple tests. No significant results were observed for OXTR rs2254298, RORA rs8042149 and CNR1 rs1049353 although the results for RORA showed a slight tendency that rs8042149 may influence the level of BSI scores in current PTSD patients. CONCLUSIONS: This study points to a role of the OXTR gene in PTSD and the related psychopathology following war related trauma.


Assuntos
Predisposição Genética para Doença , Receptor CB1 de Canabinoide/genética , Receptores de Ocitocina/genética , Receptores do Ácido Retinoico/genética , Transtornos de Estresse Pós-Traumáticos/genética , Conflitos Armados/psicologia , Bósnia e Herzegóvina , Croácia , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade
10.
Psychiatr Danub ; 31(2): 235-240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291231

RESUMO

BACKGROUND: Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. SUBJECTS AND METHODS: The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. RESULTS: No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. CONCLUSIONS: Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteína Básica da Mielina/genética , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
11.
Psychiatr Danub ; 31(2): 227-234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291230

RESUMO

BACKGROUND: Individuals who are exposed to traumatic events are at an increased risk of developing posttraumatic stress disorder (PTSD), a condition during which an individual's ability to function is impaired by emotional responses to memories of those events. The gene coding for neuropeptide Y (NPY) and the gene coding for brain-derived neurotrophic factor (BDNF) are among the number of candidate gene variants that have been identified as potential contributors to PTSD. The aim of this study was to investigate the association between NPY and BDNF and PTSD in individuals who experienced war-related trauma in the South Eastern Europe (SEE) conflicts (1991-1999). SUBJECTS AND METHODS: This study included participants with current and remitted PTSD and healthy volunteers (N=719, 232 females, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administered PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). DNA was isolated from whole blood and genotyped for NPY rs5574 via PCR - RFLP and NPY rs16147 and BDNF rs6265 using the KASP assay. RESULTS: Tests for deviation from Hardy-Weinberg equilibrium showed no significant results. Analyses at the categorical level yielded no associations between the affected individuals and all three SNPs when compared to controls. Within lifetime PTSD patients, the major alleles of both NPY variants showed a nominally significant association with higher CAPS scores (p=0.007 and p=0.02, respectively). Also, the major allele of rs5574C>T was associated with higher BSI scores with a nominal significance among current PTSD patients (p=0.047). The results did not withstand a Bonferroni adjustment (α=0.002). CONCLUSION: Nominally significant associations between NPY polymorphisms and PTSD susceptibility were found that did not withstand Bonferroni correction.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Neuropeptídeo Y/genética , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Conflitos Armados/psicologia , Europa Oriental , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
12.
Psychiatr Danub ; 31(2): 241-248, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291232

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disorder that occurs in some people who have experienced a severe traumatic event. Several genetic studies suggest that gene encoding proteins of catechol-O-methyl-transferase (COMT) may be relevant for the pathogenesis of PTSD. Some researchers suggested that the elevation of interleukin-6 (IL6) correlates with major depression and PTSD. The aim of this study was to investigate whether the single nucleotide polymorphisms COMT rs4680 (Val158Met) and IL6 rs1800795 are associated with PTSD and contribute to the severity of PTSD symptoms. SUBJECTS AND METHODS: This study comprised 747 participants that experienced war between 1991 and 1999 in the South Eastern Europe conflicts. COMT rs4680 (Val158Met) and IL6 rs1800795 genotypes were determined in 719 participants (369 with and 350 without PTSD). The Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) questionnaire and the Brief Symptom Inventory (BSI) were used for data collection. RESULTS: Regarding the COMT gene polymorphism, the results of the regression analyses for BSI total score were significant in the lifetime PTSD group in the dominant (P=0.031) and the additive allelic model (P=0.047). Regarding the IL6 gene, a significant difference was found for the recessive model predicting CAPS total score in the lifetime PTSD group (P=0.048), and indicated an association between the C allele and higher CAPS scores. n the allelic, genotypic and rezessive model, the results for BSI total score were significant in the lifetime PTSD group (P=0.033, P=0.028 and P=0.009), suggesting a correlation of the C allele with higher BSI scores. CONCLUSION: Although our nominally significant results did not withstand correction for multiple tests they may support a relevance of the COMT (Val158Met) and IL6 rs1800795 polymorphism for aspects of PTSD in war traumatized individuals.


Assuntos
Catecol O-Metiltransferase/genética , Interleucina-6/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Conflitos Armados/psicologia , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Psychiatr Danub ; 31(2): 256-262, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291234

RESUMO

BACKGROUND: Post-traumatic stress disorder (PTSD) is a stress related disorder which can occur in an individual after exposure to a traumatic event. It most commonly co-occurs with depression. The two disorders share not only overlapping symptoms, but also genetic diathesis. The aim of this study was to investigate the potential role of single nucleotide polymorphisms (SNPs) of the two serotonergic candidate genes 5-hydroxytryptamine receptor 1A (HTR1A) and tryptophan hydroxylase 2 (TPH2) in the pathogenesis of PTSD and comorbid psychopathology. SUBJECTS AND METHODS: 719 (487 males, 232 females) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Herzegovina, Kosovo and Croatia were included in the study. The Sociodemographic questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I.), Clinician Administered PTSD Scale (CAPS) and Brief Symptom Inventory (BSI) were used to collect clinical data. The SNPs rs6295 (HTR1A), rs11178997 and rs1386494 (TPH2) were investigated for their association with PTSD and comorbid psychopathology. RESULTS: A nominal significant association was found between the BSI total score in Lifetime PTSD with the SNP rs6295 of the HTR1A gene. The best result was seen in the dominant model (P=0.018), with the minor allele (C) being the risk allele. Several BSI subscores were also associated with the minor (C) allele in Lifetime PTSD. No association was found for the TPH2 SNPs rs11178997 and rs1386494 in relation to PTSD or comorbid psychopathology. CONCLUSIONS: Our findings suggest that rs6295 in the HTR1A gene may contribute to the psychopathology of PTSD.


Assuntos
Alelos , Receptor 5-HT1A de Serotonina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Triptofano Hidroxilase/genética , Conflitos Armados/psicologia , Bósnia e Herzegóvina , Croácia , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade
14.
Psychiatr Danub ; 31(2): 263-268, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291235

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex stress related disorder, that follows a severe traumatic experience, characterized with an intense sense of terror, fear, and helplessness. The aim of this study is to identify associations of genetic variations within candidate genes DRD2 and DRD4 with various PTSD related phenotypes. PTSD lifetime and PTSD current subjects were analyzed separately, each of them were analyzed in a Case/Control design, as well as regarding BSI and CAPS within cases only. SUBJECTS AND METHODS: 719 (487 male, 232 female) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Hercegovina, Kosovo and Croatia were included in the study. Sociodemographic questionnaire, Clinician Administered PTSD Scale (CAPS) and the Brief Symptom Inventory (BSI) were used to collect clinical data. RESULTS: The DRD2 rs1800497 variant and a variable number tandem repeat (VNTR) located in exon three of DRD4 were investigated for association with PTSD. In case control analyses we did not identify any significant associations. Within the PTSD current patients, we identified an association of DRD2 rs1800497 with BSI in the genotypic and the recessive model with the T allele as the risk allele. CONCLUSION: Our findings suggest that rs1800497 of DRD2 gene is involved in pathogenesis of PTSD.


Assuntos
Repetições Minissatélites , Polimorfismo Genético , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genética , Transtornos de Estresse Pós-Traumáticos/genética , Conflitos Armados/psicologia , Bósnia e Herzegóvina , Croácia , Éxons/genética , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade
15.
Psychiatr Danub ; 31(2): 269-275, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291236

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly frequent and disabling psychiatric condition among war-affected populations. The FK506-binding protein 5 (FKBP5) gene and the corticotropin-releasing hormone receptor 1 (CRHR1) gene have previously been implicated in an elevated risk of peritraumatic dissociation and PTSD development. Our aim was to investigate the association between FKBP5 and CRHR1 genotypes and PTSD diagnosis and severity among individuals who were affected by the Balkan wars during the 1990s. SUBJECTS AND METHODS: This study included participants with current PTSD, remitted PTSD and healthy volunteers (N=719, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). FKBP5 rs1360780 and CRHR1 rs17689918 genotypes were determined using a KASP genotyping assay. RESULTS: Tests for deviation from Hardy Weinberg equilibrium showed no significant results. Logistic and linear regression was used to examine the associations between the FKBP5 SNP rs1360780 and the CRHR1 SNP rs17689918 with PTSD diagnosis and severity, as well as general psychiatric symptom severity, separately for current and remitted PTSD patients. There were nominally significant associations under a dominant model between the rs1360780 C allele and PTSD diagnosis as well as symptom severity, which however, were not significant anymore after Bonferroni adjustment (α=0.002). For CRHR1 rs17689918 no significant associations were detected. CONCLUSION: We found nominally, but not Bonferroni corrected significant associations between the FKBP5 polymorphism rs1360780 and PTSD susceptibility among individuals affected by the Balkan wars. For elucidating this gene's real resilience/vulnerability potential, environmental influences should be taken into account.


Assuntos
Conflitos Armados/psicologia , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único , Receptores de Hormônio Liberador da Corticotropina/genética , Transtornos de Estresse Pós-Traumáticos/genética , Proteínas de Ligação a Tacrolimo/genética , Europa Oriental , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Int J Neuropsychopharmacol ; 21(9): 822-827, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169842

RESUMO

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.


Assuntos
Metilação de DNA , Terapia Implosiva , Monoaminoxidase/metabolismo , Transtornos Fóbicos/metabolismo , Transtornos Fóbicos/terapia , Adulto , Ansiedade/genética , Ansiedade/metabolismo , Ansiedade/terapia , Ilhas de CpG , Epigênese Genética , Extinção Psicológica/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Monoaminoxidase/genética , Transtornos Fóbicos/genética , Resultado do Tratamento
17.
Int J Neuropsychopharmacol ; 21(5): 423-432, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186431

RESUMO

Background: Posttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity. Methods: Monoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters. Results: In the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D). Conclusions: The present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Monoaminoxidase/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Bósnia e Herzegóvina , Croácia , Feminino , Humanos , Kosovo , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores Sexuais
18.
J Neural Transm (Vienna) ; 125(11): 1581-1588, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30242487

RESUMO

Epigenetic processes such as DNA methylation are considered key mechanisms at the crossroads between genetics and environment in the etiology of mental disorders. The monoamine oxidases A and B (MAOA/MAOB) are prime candidates for the investigation into the role of DNA methylation in mental disorders, given their pivotal role in the metabolism of monoamines and as pharmacological targets of potent antidepressant drugs such as tranylcypromine, phenelzine or moclobemide. The present mini-review aims at summarizing and critically discussing the growing body of the literature supporting a role of DNA methylation of the MAOA gene promoter/exon I/intron I region and its interaction with environmental factors in several mental disorders, i.e., anxiety disorders, depression, posttraumatic stress disorder, substance use disorder, conduct disorder/antisocial personality disorder, borderline personality disorder and schizophrenia, as well as some pilot data on MAOB methylation in smokers and patients with borderline personality disorder. Furthermore, first evidence for MAOA methylation to be involved in treatment response prediction and as a potential mechanistic correlate of fear extinction is presented. Altered MAOA gene DNA methylation emerges as a possible pathogenetically relevant epigenetic mechanism in mental disorders. Given robust replication and further functional characterization, MAOA methylation patterns might serve as a peripheral biomarker of disease risk and treatment response informing preventive and personalized therapeutic approaches in the future.


Assuntos
Metilação de DNA , Predisposição Genética para Doença , Transtornos Mentais/genética , Monoaminoxidase/genética , Epigênese Genética , Humanos , Regiões Promotoras Genéticas
19.
Nervenarzt ; 89(11): 1303-1314, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30302516

RESUMO

Epigenetic mechanisms, such as DNA methylation and histone modifications are biochemical alterations of the DNA or its spatial structure. They regulate gene function, can be modified by environmental influences and are temporally dynamic. In this review, the current state of knowledge regarding the role of epigenetics in the pathogenesis of mental disorders is summarized exemplarily for schizophrenia, depression, anxiety disorders and posttraumatic stress disorder. Additionally, findings on epigenetic alterations in the course of pharmacotherapeutic and psychotherapeutic interventions are presented. Epigenetic mechanisms have a central function at the crossroads between genes and environment and consequently in the vulnerability-stress model of mental disorders. Prospectively, in line with a precision medicine approach epigenetic profiles may represent useful markers of disease risk and therapy response or even constitute new druggable targets.


Assuntos
Epigênese Genética , Transtornos Mentais , Metilação de DNA , Humanos , Transtornos Mentais/genética , Transtornos Mentais/patologia , Esquizofrenia/genética , Esquizofrenia/patologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/patologia
20.
Electrophoresis ; 38(21): 2771-2776, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28758677

RESUMO

We present a simple method to estimate the isoelectric point (pI) of Tomato Bushy Stunt particles. We demonstrate that the combination of agarose gels with different pH buffers can be used to electrophorese the virus particles and their migration patterns can be compared. This method allows us to estimate the pI of the virus particles (wild type, wt, and genetically modified particles) and to monitor the effect of the pI of modified peptide side chains of the viral capsid subunit on the pI of the whole virus particle.


Assuntos
Tombusvirus/química , Vírion/química , Soluções Tampão , Proteínas do Capsídeo/química , Difusão , Eletroforese em Gel de Ágar , Concentração de Íons de Hidrogênio , Ponto Isoelétrico , Peptídeos/química , Propriedades de Superfície , Tombusvirus/isolamento & purificação , Vírion/isolamento & purificação
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