myelin-basic-protein and Mental-Disorders

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

Topics: Age Factors; Analysis of Variance; Animals; Antigens, CD; Cell Adhesion Molecules; Chelating Agents; Cohort Studies; Corpus Callosum; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Mental Disorders; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Oligodendroglia

Discoidin domain receptor 1 (DDR1) is expressed in myelin oligodendrocytes and co-localizes with myelin basic protein (MBP). Alternative splicing of DDR1 generates five isoforms designated DDR1a-e. The MBP mRNA contains an hnRNP A2 response element (A2RE) sequence that is recognized by heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, which is responsible for transport of the MBP mRNA to oligodendrocyte processes. We hypothesized that DDR1 could have a functional A2RE sequence. By in silico analysis, we identified an A2RE-like sequence in the human DDR1 mRNA. We observed nuclear and dendrite cytoplasmic immunofluorescence, indicating that DDR1 and hnRNP A2/B1 co-localize in human oligodendrocytes and in differentiated HOG16 cells. The A2RE-like sequence of DDR1 contains the single nucleotide polymorphism rs2267641, and we found that in the human brain, the minor allele is associated with lower and higher levels DDR1b and DDR1c mRNA expression, respectively. Moreover, a positive correlation between DDR1c and the myelin genes myelin-associated glycoprotein and oligodendrocyte lineage transcription factor 2 was found. Differentiated HOG16 cells transfected with an hnRNP A2/B1 siRNA simultaneously show a decrease and an increase in the DDR1c and DDR1b mRNA expression levels, respectively, which was accompanied by a decrease in DDR1 protein levels at the cytoplasmic edges. These results suggest that the DDR1 A2RE sequence is functionally involved in the hnRNP A2/B1-mediated splicing and transport of the DDR1c mRNA.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Line, Transformed; Discoidin Domain Receptors; Gene Expression Regulation; Genotype; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Humans; Mental Disorders; Microscopy, Confocal; Myelin Basic Protein; Nerve Tissue Proteins; Occipital Lobe; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Polymorphism, Single Nucleotide; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Receptors, Mitogen; Response Elements; RNA Transport; RNA, Messenger; RNA, Small Interfering; Transfection

Abnormalities of proteins involved in neurotransmission and neural plasticity at synapses are reported in schizophrenia, and may be markers of dysregulated neural connectivity in this illness. Studies of brain development and neural regeneration indicate a dynamic interplay between neural and oligodendroglial mechanisms in regulating synaptic plasticity and axonal sprouting. In the present study, markers of synapses (synaptophysin), plasticity (growth-associated protein-43) and oligodendrocytes (myelin basic protein) were investigated in anterior frontal cortex homogenates from individuals with schizophrenia and depression. Synaptophysin immunoreactivity was reduced in schizophrenics who died of natural causes relative to controls. Myelin basic protein immunoreactivity was decreased in both schizophrenics and depressed individuals who died by suicide. Overall, no changes were observed in growth-associated protein-43 immunoreactivity. However, a slight increase in immunoreactivity in depressed suicides relative to control was observed. These findings support the hypothesis that synaptic abnormalities are a substrate for disordered connectivity in severe mental illness, and suggest that synaptic-oligodendroglial interactions may contribute to the mechanism of dysregulation in certain cases.

Topics: Adult; Aged; Enzyme-Linked Immunosorbent Assay; Female; Frontal Lobe; GAP-43 Protein; Humans; Immunoblotting; Immunohistochemistry; Male; Mental Disorders; Middle Aged; Myelin Basic Protein; Nerve Tissue Proteins; Neuronal Plasticity; Synapses

Sera from psychiatric patients (32 with senile dementia, 56 with Alzheimer's disease, 189 with schizophrenia, 117 with manic-depressive psychoses, 52 with other nonorganic psychoses, 44 with paranoid state, 58 with neurotic depression and 78 with alcoholic syndrome), normal subjects (112 blood donors) and 43 hospitalized elderly patients with chronic cardiac failures without senile syndrome were examined by means of an enzyme-linked immunosorbent assay (ELISA) for the presence of autoantibodies to human brain S100 protein, neuron specific enolase (NSE) and myelin basic protein (MBP). These varied antibrain autoantibodies occurred at different frequencies. The highest incidence of anti-S100 and anti-NSE antibodies was in Alzheimer's disease and senile dementia, than in manic-depressive and other nonorganic psychoses, and the lowest in paranoid state, neurotic depression, schizophrenia and alcoholic syndrome. The frequency of anti-S100 autoantibodies was higher than that of anti-NSE. Autoantibodies reacting with MBP were revealed in a very small number of psychiatric patients. In healthy individuals and control cardiac patients, the incidence of antibrain autoantibodies was low. These results suggest a differential correlation between antibrain autoantibodies and psychiatric diseases.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Brain; Enzyme-Linked Immunosorbent Assay; Female; Heart Diseases; Humans; Male; Mental Disorders; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Proteins

Circulating lymphocyte populations were examined in 85 patients with multiple sclerosis (MS), 26 of whom showed exacerbations; 48 patients with other neurological diseases (OND); 14 patients suffering from psychiatric disorders; and 2 normal subjects. The study involved the assay of early (active, high-affinity rosetting) T-cells, myelin basic protein (MBP)-reactive early T-cells, late (total, 24-hour rosetting) T-cell levels were significantly lower in MS (p less than 0.01) than in OND subjects. Exacerbations in MS were usually accompanied by further decreases in early T-cells. The lower levels of early T-cells in MS and their fluctuations are believed to reflect disease activity. MBP-reactive early T-cells were more frequently increased in MS (75% of cases) than OND (50%), and while this might be indicative of increased sensitization against myelin antigens, it was found not to be an MS-specific phenomenon.

Topics: Adult; B-Lymphocytes; Female; Humans; Immunity, Cellular; Male; Mental Disorders; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Remission, Spontaneous; T-Lymphocytes