| 1 | Front Psychiatry 2010 -1 1: 19 |
|---|---|
| PMID | 21423430 |
| Title | Low Density Lipoprotein Receptor-Related Protein and Apolipoprotein E Expression is Altered in Schizophrenia. |
| Abstract | Our recent microarray study reported altered mRNA expression of several low density lipoprotein receptor-related proteins (LRP) associated with the first 4 years following diagnosis withschizophrenia. Whilst this finding is novel, apolipoprotein E (APOE), which mediates its activity through LRPs, has been reported by several studies to be altered in brains of subjects withschizophrenia. We used qPCR to measure the expression of LRP2, LRP4, LRP6,LRP8, LRP10 and LRP12 mRNA in Brodmann's area (BA) 46 of the dorsolateral prefrontal cortex in 15 subjects with short duration of illnessschizophrenia(SDS) and 15 pair matched controls. We also used Western blotting to measure APOE protein expression in BA46 from these subjects. Amongst the LRPs examined, LRP10 expression was significantly increased (P?=?0.03) and LRP12 was significantly decreased (P?schizophreniaand adds weight to the hypothesis that aberrant apolipoprotein signaling is involved in the early stages ofschizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Nature 2011 Apr 472: 356-60 |
| PMID | 21460838 |
| Title | Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. |
| Abstract | Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known asLRP8). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and it has also been associated with other neurological disorders such as epilepsy,schizophrenia和阿尔茨海默氏症。的分子机制by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln(+/-); Efnb3(-/-) or Reln(+/-); Efnb2(-/-)) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system. |
| SCZ Keywords | schizophrenia |
| 3 | Mol Autism 2012 -1 3: 11 |
| PMID | 23110844 |
| Title | Vldlr overexpression causes hyperactivity in rats. |
| Abstract | Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr andLRP8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism,schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients. We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features. Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function. Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities. |
| SCZ Keywords | schizophrenia |
| 4 | Mol. Neurobiol. 2015 Dec -1: -1 |
| PMID | 26637325 |
| Title | 支持LRP8收敛的证据s a Susceptibility Gene for Psychosis. |
| Abstract | Reelin (RELN) is identified as a risk gene for major psychiatric disorders such asschizophrenia(SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whetherLRP8is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) inLRP8in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 inLRP8significantly associated with SCZ and BPD as well as the combined psychosis phenotype (P meta?=?1.99?�?10(-5), odds ratio (OR)?=?1.066, 95�% confidence interval (CI)?=?1.035-1.098). The risk SNP rs5174 was also associated withLRP8messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P?=?0.00005). Further exploratory analysis revealed thatLRP8was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated thatLRP8significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P?=?7.0?�?10(-4)). Collectively, we confirmed thatLRP8is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involvingLRP8underlying risk of complex psychiatric disorders. |
| SCZ Keywords | schizophrenia |