| 1 | J. Neurol. Neurosurg. Psychiatr. 2007 May 78: 532-5 |
|---|---|
| PMID | 17202228 |
| Title | Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. |
| Abstract | To investigate a possible association of mutations in the PTEN-induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism. 20 members of a family (4 homozygous, 11 heterozygous and 5 non-mutation carriers) were investigated for the presence of psychiatric disorders using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV); information on three additional heterozygous mutation carriers was obtained according to the family history research diagnostic criteria. We found predominantly affective and schizophrenia spectrum disorders in 11 (61%) of the 18 mutation carriers and in 1 (20%) of the 5 mutation-negative cases. First, affective and psychotic symptoms may be part of the phenotypic spectrum or even the sole manifestation of PINK1 mutations. Second, patients with familial movement disorders associated with psychiatric conditions may serve as a valuable study population to explore (genetic) causes of neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | PLoS ONE 2011 -1 6: e20198 |
| PMID | 21647420 |
| Title | Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex. |
| Abstract | Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated. We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Am. J. Med. Genet. A 2013 Dec 161A: 2931-7 |
| PMID | 24039187 |
| Title | The AKT genes and their roles in various disorders. |
| Abstract | AKT (AK mouse plus Transforming or Thymoma) is a common oncogene expressed in most tissues. Both AKT2 and AKT3, although important, have more limited distributions. The regulation of all three genes depends on two receptors-a receptor tyrosine kinase with a growth factor ligand, and a G protein coupled receptor, also with a ligand together with an explanation of how their downsteam components function. AKT2 is amplified or overexpressed in cancer with a higher frequency than those found with AKT1. AKT1 is cardioprotective to the heart by supporting its physiological growth and function. AKT2 is closely linked to Type II diabetes and the implications of various types of mutations are discussed. Various AKT3 mutations are important in neurological disorders, such as microcephaly, hemimegalencephaly, and megalencephaly syndromes. Finally, a reduced level of AKT1 in the frontal cortex has been found during post-mortem brain studies of schizophrenic patients in the populations of many countries. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Mol. Psychiatry 2013 Dec 18: 1249-64 |
| PMID | 23958961 |
| Title | Discovery and validation of blood biomarkers for suicidality. |
| Abstract | Suicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner's office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Toxicol. Sci. 2013 Mar 132: 196-210 |
| PMID | 23288049 |
| Title | Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. |
| Abstract | Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and 2,2',4,5'-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain. |
| SCZ Keywords | schizophrenia, schizophrenic |