alpha-synuclein and Schizophrenia

The final common pathway in the etiopathogenesis of schizophrenia is suggested that there is a defect in the presynaptic terminal in dopaminergic transmission, in which α-synuclein has an important role. Peripheral biomarker studies in schizophrenia have become crucial for better diagnoses, early interventions, and personalized therapies. This study aims to compare α-synuclein levels in patients with schizophrenia and their unaffected siblings with healthy controls, as a potential peripheral biomarker for schizophrenia.. The quantifications of α-synuclein serum concentrations were conducted by the ELISA method. PANSS and CGI-S were used to analyse the severity of the symptoms of the subjects. Data were analysed by nonparametric tests and the Receiver Operating Curve (ROC) analysis.. Sixty-two patients with schizophrenia (mean age: 34,8 ± 9,9, %64,5 male), their 56 unaffected siblings (mean age: 39,4 ± 11,5, %55,4 male) and 56 healthy controls (mean age: 36,2 ± 9,8, %64,3 male) were included. α-synuclein levels were significantly lower in the patient (27,65 (12,61-46,09) pg/ml) and the unaffected sibling groups (24,62 (15,60-57,87) pg/ml) compared with healthy controls (45,58 (11,25-108,30) pg/ml) (p < .001). According to the ROC analysis, the optimal cut-off value for α-synuclein levels in distinguishing the schizophrenia group from the control group was 42.20. The sensitivity of the measurement of serum α-synuclein at this point was 93.5%, and the specificity was 60.7%.. Our study demonstrates that decreased levels of serum α-synuclein may be utilized as a possible peripheral biomarker of familial risk for schizophrenia in both patients and their siblings.

Topics: Adult; alpha-Synuclein; Biomarkers; Female; Health Status; Humans; Male; Middle Aged; Schizophrenia; Siblings; Young Adult

We have often observed dementia symptoms or severe neurocognitive decline in the long-term course of schizophrenia. While there are epidemiological reports that patients with schizophrenia are at an increased risk of developing dementia, there are also neuropathological reports that the prevalence of Alzheimer's disease (AD) in schizophrenia is similar to that in normal controls. It is difficult to distinguish, based solely on the clinical symptoms, whether the remarkable dementia symptoms and cognitive decline seen in elderly schizophrenia are due to the course of the disease itself or a concomitant neurocognitive disease. Neuropathological observation is needed for discrimination.. We conducted a neuropathological search on three cases of schizophrenia that developed cognitive decline or dementia symptoms after a long illness course of schizophrenia. The clinical symptoms of total disease course were confirmed retrospectively in the medical record. We have evaluated neuropathological diagnosis based on not only Hematoxylin-Eosin and Klüver-Barrera staining specimens but also immunohistochemical stained specimens including tau, β-amyloid, pTDP-43 and α-synuclein protein throughout clinicopathological conference with multiple neuropathologists and psychiatrists.. The three cases showed no significant pathological findings or preclinical degenerative findings, and poor findings consistent with symptoms of dementia were noted.. Although the biological background of dementia symptoms in elderly schizophrenic patients is still unclear, regarding the brain capacity/cognitive reserve ability, preclinical neurodegeneration changes in combination with certain brain vulnerabilities due to schizophrenia itself are thought to induce dementia syndrome and severe cognitive decline.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Brain; Cognitive Dysfunction; Dementia; Diagnosis; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Lewy Bodies; Male; Middle Aged; Neuropathology; Prevalence; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; tau Proteins; Tomography, X-Ray Computed

Previous studies suggested that the alpha-synapse protein (SNCA) gene and its coding product α-synuclein (α-Syn) may play a role in the pathogenesis of neurodegenerative diseases. The mutation of SNCA can influence the formation of nerve fibers and the function of dopaminergic neurons, and that may be related to addictive behavior, such as alcohol dependence. SNCA may overlap with the pathogenesis of schizophrenia and Parkinson's disease or alcohol dependence associated with the dopamine pathway. The aim was to determine the association between three SNCA SNPs (rs3822086C/T, rs11931074G/T, and rs356219A/G) and schizophrenia in a Chinese North Han population.. A total of 878 subjects, with or without schizophrenia, were included in our study. DNA purification, Polymerase Chain Reaction (PCR) amplification, and subsequent restriction fragment length polymorphism (RFLP) analysis were manipulated to determine genotypes.. Between the schizophrenia group and healthy group, neither the genotype nor allele frequencies of rs3822086C/T, rs11931074G/T, or rs356219A/G differed significantly in either the total sample or the subgroups. In the haplotype analysis, the ATT and GTT haplotype frequencies differed significantly between the patients and controls in the total sample (χ2=6.052, p=0.0139; χ2=4.508, p=0.0337). In the female subgroup, the ATT haplotype frequency differed significantly between the patients and controls (χ2=4.219, p=0.04).. There was no association between SNCA polymorphisms and schizophrenia in the North Han Chinese population, and the ATT haplotype may be a susceptibility factor for schizophrenia.

Topics: Adolescent; Adult; alpha-Synuclein; Asian People; Ethnicity; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Schizophrenia; Young Adult

We present the case of a patient who developed delusions and auditory hallucinations and was clinically diagnosed as having schizophrenia. Ten years after the onset of schizophrenia, the disease progressed to mild parkinsonism. SNCA duplication was confirmed. This case expands the spectrum of clinical features in carriers of SNCA duplication.

Topics: Adult; alpha-Synuclein; Humans; Male; Parkinson Disease; Pedigree; Prodromal Symptoms; Schizophrenia

To study the relationship between neurodegenerative diseases including argyrophilic grain disease (AGD) and late-onset schizophrenia and delusional disorders (LOSD; onset ≥40 years of age), we pathologically examined 23 patients with LOSD, 71 age-matched normal controls, and 22 psychiatric disease controls (11 depression, six personality disorder, two bipolar disorders, and three neurotic disorders cases). In all LOSD cases (compared to age-matched normal controls), the frequencies of Lewy body disease (LBD), AGD, and corticobasal degeneration (CBD) were 26.1 % (11.3 %), 21.7 % (8.5 %), and 4.3 % (0.0 %), respectively. There was no case of pure Alzheimer's disease (AD). The total frequency of LBD, AGD, and CBD was significantly higher in LOSD cases than in normal controls. Argyrophilic grains were significantly more severe in LOSD than in controls, but were almost completely restricted to the limbic system and adjacent temporal cortex. In LOSD patients whose onset occurred at ≥65 years of age (versus age-matched normal controls), the frequencies of LBD and AGD were 36.4 % (19.4 %) and 36.4 % (8.3 %), respectively, and AGD was significantly more frequent in LOSD patients than in normal controls. In LOSD patients whose onset occurred at <65 years of age, the frequencies of LBD, AGD, and CBD were 16.7, 8.3, and 8.3 %, comparable to those of age-matched normal controls (10.2, 5.1, and 0.0 %). In all psychiatric cases, delusion was significantly more frequent in AGD cases than in cases bearing minimal AD pathology alone. Given these findings, LOSD patients may have heterogeneous pathological backgrounds, and AGD may be associated with the occurrence of LOSD especially after 65 years of age.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; alpha-Synuclein; Brain; Case-Control Studies; DNA-Binding Proteins; Female; Humans; Intermediate Filaments; Male; Middle Aged; Neurodegenerative Diseases; Psychotic Disorders; Schizophrenia; Statistics, Nonparametric; tau Proteins

Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions.

Topics: Acoustic Stimulation; Age Factors; alpha-Synuclein; Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Benzamides; Benzazepines; Biogenic Monoamines; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Agents; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Gait Disorders, Neurologic; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Heme Oxygenase-1; Homeodomain Proteins; Humans; Inhibition, Psychological; Laser-Doppler Flowmetry; Mice; Mice, Transgenic; MicroRNAs; Nuclear Receptor Subfamily 4, Group A, Member 2; Protein Binding; Receptors, Dopamine D1; Receptors, Dopamine D2; Reelin Protein; RNA, Messenger; Schizophrenia; Sensory Gating; Superoxide Dismutase; Transcription Factors; Tritium; Tyrosine 3-Monooxygenase

Alpha-synuclein is largely, but not entirely, expressed in the central nervous system. A high concentration of alpha-synuclein in presynaptic terminals can mimic the normal function of endogenous alpha-synuclein in regulating synaptic vesicle mobilization at nerve terminals. Beta-synuclein protein is seen primarily in brain tissue and it is suggested that beta-synuclein acts as an inhibitor of alpha-synuclein aggregation, which occurs in neurodegenerative diseases. With respect to the role of synucleins in neurologic diseases such as Parkinson's disease, we decided to study the changes of alpha- and beta-synucleins in schizophrenia patients in relation to a control group. For this purpose, total RNA was extracted from the lymphocytes of patients and controls and then cDNA was synthesized and used for real-time polymerase chain reaction. Calculation of the relative expression of alpha- and beta-synucleins showed downregulation in patients in comparison to the control group. Independent two-tailed t-test showed that beta-synuclein mRNA expression in the control group was significantly higher than that in the patient group (p < 0.01), but downregulation of alpha-synuclein gene was not significant. Therefore, a significant downregulation of beta-synuclein mRNA expression appears to be a suitable biomarker for the diagnosis of schizophrenia.

Topics: Adult; Aged; alpha-Synuclein; beta-Synuclein; Biomarkers; Case-Control Studies; Down-Regulation; Female; Gene Expression Regulation; Humans; Lymphocytes; Male; Middle Aged; RNA, Messenger; Schizophrenia

The role of alpha-synuclein (alphaSyn) in schizophrenia is unknown, whereas in a recent animal model of depression, alpha- and gamma-synuclein have been related to its pathophysiology. Previous biochemical studies in Brodmann area 9 showed significant reduction of alphaSyn in both chronic schizophrenia and bipolar disorder. Here, prevalence and cerebral distribution of alphaSyn were examined in 80 autopsy cases of elderly subjects (41 chronic schizophrenia, 12 late live depression/LLD and bipolar disorder/BD, and 27 age-matched controls without neuropsychiatric disorders). Using immunohistochemistry, alphaSyn-positive lesions (Lewy bodies and neurites) were assessed semiquantitatively. Among 41 chronic schizophrenics, all except one showing low neuritic Braak stages (mean 1.46), three brains (7.3%) revealed only few alphaSyn-positive inclusions restricted to medullary nuclei. Among 12 LLD and BD patients with mean Braak stage 2.25, alphaSyn-positive pathology was seen in two cases (16.7%) with clinical LLD, but none in BD. Among 27 controls, showing mean neuritic Braak stage 2.6, seven brains (26%) with higher mean age showed alphaSyn-positive lesions, either isolated in substantia nigra and nucleus basalis of Meynert (n = 2 each), in medullary nuclei, locus ceruleus and substantia nigra (n = 2), with additional involvement of nucleus basalis (n = 1). This first preliminary study in non-demented psychiatric disorders indicates that alphaSyn/Lewy pathology in chronic schizophrenia is significantly less frequent than in clinically healthy elderly people (P < 0.01), showing 10-30% of so-called incidental Lewy body disease. Among chronic affective disorders, according to our small cohort, the incidence of Lewy-pathology in LLD appears to be comparable to a healthy elderly population, whereas its occurence in BD is to be elucidated.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Autopsy; Bipolar Disorder; Brain; Depressive Disorder, Major; Female; Humans; Lewy Bodies; Male; Middle Aged; Schizophrenia

Abnormalities in the size and activity of the insular cortex (IC), a brain region involved in auditory hallucinations and language, have been previously found in brain imaging studies in schizophrenia. In addition, cortical layer 2 has been shown to be abnormal in many brain regions in schizophrenia. In this study, 2-D DIGE was used to quantitatively analyse protein expression in schizophrenia and control cases (n = 15/group) in microdissected layer 2 IC tissue. Proteomic analyses revealed 57 significantly differentially expressed (p<0.05) protein spots in schizophrenia. Validation of differential expression of two of the proteins differentially expressed was subsequently confirmed using Western blotting. This work provides evidence of abnormal protein expression in layer 2 of the IC in schizophrenia, supporting previous work of reduced neuronal size in this cortical layer in the IC. Over half of proteins abnormally expressed in this study have not been reported previously in proteomic studies investigating schizophrenia or neurodegenerative disorders. Proteins found to be abnormally expressed appear to collectively impact on neuronal plasticity through roles in neurite outgrowth, cellular morphogenesis and synaptic function.

Topics: alpha-Synuclein; Blotting, Western; Cerebral Cortex; Demography; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Mass Spectrometry; Microdissection; Middle Aged; Nerve Tissue Proteins; Neuronal Plasticity; Proteome; Proteomics; Schizophrenia

In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls.. Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction.. In BPDI, levels of SNAP-25 (p < 0.01) and synaptophysin (p < 0.05) increased. There were no changes in schizophrenia or any other changes in BPDI. Levels of mRNA for SNAP-25 were decreased in BPDI (p < 0.05).. Changes in SNAP-25 and synaptophysin in BPDI suggest that changes in specific neuronal functions could be linked to the pathology of the disorder.

Topics: alpha-Synuclein; Antibodies; Bipolar Disorder; Cell Adhesion Molecules; Cell Culture Techniques; Dynamin I; Female; Humans; Male; Middle Aged; Polymerase Chain Reaction; Prefrontal Cortex; Qa-SNARE Proteins; R-SNARE Proteins; RNA, Messenger; Schizophrenia; Synaptophysin; Synaptosomal-Associated Protein 25