Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Molecular Psychiatry (Impact Factor: 14.5). 12/2005; 10(11):1045-55. DOI: 10.1038/
Source: PubMed


We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

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    • "For instance, acute and chronic METH-induced hyperlocomotion and PPI were less severe in Pdlim5+/− than in Pdlim5+/+ mice. These findings suggest that lower levels of PDLIM5 prevent the development of a manic state or schizophrenia, which is consistent with the speculation from the observations in human postmortem brains, because higher levels of PDLIM5 have been reported in the prefrontal cortex of patients with schizophrenia and bipolar disorders [10], [19]. The mechanisms for these findings are subject to speculation. "
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    ABSTRACT: Reports indicate that PDLIM5 is involved in mood disorders. The PDLIM5 (PDZ and LIM domain 5) gene has been genetically associated with mood disorders; it's expression is upregulated in the postmortem brains of patients with bipolar disorder and downregulated in the peripheral lymphocytes of patients with major depression. Acute and chronic methamphetamine (METH) administration may model mania and the evolution of mania into psychotic mania or schizophrenia-like behavioral changes, respectively. To address whether the downregulation of PDLIM5 protects against manic symptoms and cause susceptibility to depressive symptoms, we evaluated the effects of reduced Pdlim5 levels on acute and chronic METH-induced locomotor hyperactivity, prepulse inhibition, and forced swimming by using Pdlim5 hetero knockout (KO) mice. The homozygous KO of Pdlim5 is embryonic lethal. The effects of METH administration on locomotor hyperactivity and the impairment of prepulse inhibition were lower in Pdlim5 hetero KO mice than in wild-type mice. The transient inhibition of PDLIM5 (achieved by blocking the translocation of protein kinase C epsilon before the METH challenge) had a similar effect on behavior. Pdlim5 hetero KO mice showed increased immobility time in the forced swimming test, which was diminished after the chronic administration of imipramine. Chronic METH treatment increased, whereas chronic haloperidol treatment decreased, Pdlim5 mRNA levels in the prefrontal cortex. Imipramine increased Pdlim5 mRNA levels in the hippocampus. These findings are partially compatible with reported observations in humans, indicating that PDLIM5 is involved in psychiatric disorders, including mood disorders.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "One important factor that could affect gene expression is genetic polymorphism. To examine the effect of SNPs on the expression level of PDLIM5 mRNA in untreated BPD, we genotyped four SNPs of PDLIM5 that have previously been found to be significantly associated with BPD [6,7]. We observed no significant correlation between these four SNPs, located in the upstream region of the PDLIM5 gene, with PDLIM5 mRNA expression in peripheral leukocytes. "
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    ABSTRACT: Background One of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is PDLIM5, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on PDLIM5 mRNA expression in the peripheral blood leukocytes of BPD patients. Methods We measured the expression of PDLIM5 mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real-time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared PDLIM5 mRNA expression in treatment-naïve BPD patients with that in healthy control subjects. Results No significant difference was found in PDLIM5 mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (p>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (p<0.05), the effectiveness of the medication did not significantly correlate with the expression of PDLIM5 mRNA (p>0.05). Interestingly, PDLIM5 mRNA expression differed significantly between treatment-naïve BPD patients and healthy control subjects (p=0.002). Conclusion PDLIM5 mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of PDLIM5 mRNA in the peripheral blood leukocytes of treatment-naïve BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD.
    Full-text · Article · Oct 2012 · BMC Medical Genetics
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    • "Furthermore, single nucleotide polymorphisms (SNPs) in PDLIM5 have been linked to schizophrenia (Horiuchi et al., 2006; Li et al., 2008), major depressive disorder (Liu et al., 2008), and bipolar disorder (Kato et al., 2005), suggesting that PDLIM5 may be a general susceptibility gene for psychiatric illnesses. Certain SNPs located within the 5′ untranslated region of PDLIM5 are associated with increased levels of PDLIM5 expression (Horiuchi et al., 2006), and mRNA levels of PDLIM5 have been found to be elevated in post-mortem brains of patients with schizophrenia, bipolar disorder, and major depression (Iwamoto et al., 2004a; Iwamoto et al., 2004b; Kato et al., 2005). Mimicking this upregulation by overexpressing PDLIM5 in cultured hippocampal neurons resulted in excessively thin dendritic spines. "
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    ABSTRACT: Dendritic spine morphology is thought to play important roles in synaptic development and plasticity, and morphological derangements in spines are correlated with several neurological disorders. Here, we identified an interaction between Spine-Associated RapGAP (SPAR), a postsynaptic protein that reorganizes actin cytoskeleton and drives dendritic spine head growth, and PDLIM5/Enigma Homolog (ENH), a PDZ-LIM (postsynaptic density-95/Discs large/zona occludens 1-Lin11/Isl-1/Mec3) family member. PDLIM5 has been implicated in susceptibility to bipolar disorder, major depression, and schizophrenia, but its function in neurological disease is poorly understood. We show that PDLIM5 is present in the postsynaptic density, where it promotes decreased dendritic spine head size and longer, filopodia-like morphology. Conversely, RNA interference against PDLIM5 or loss of PDLIM5 interaction with SPAR caused increased spine head diameter. Furthermore, PKC activation promoted delivery of PDLIM5 into dendritic spines and increased its spine colocalization with SPAR. These data reveal new postsynaptic functions for PDLIM5 in shrinkage of dendritic spines that may be relevant to its association with psychiatric illness.
    Full-text · Article · Nov 2009 · Molecular and Cellular Neuroscience
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