Publications (6) View all
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Article: GRIK4/KA1 protein expression in human brain and correlation with bipolar disorder risk variant status.
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ABSTRACT: The kainate class of ionotropic glutamate receptors is involved in the regulation of neuronal transmission and synaptic plasticity. Previously we reported that a deletion variant within the gene GRIK4, which encodes the KA1 kainate receptor subunit, was associated with a reduced risk of bipolar disorder and increased GRIK4 mRNA abundance. Using a high resolution immunohistochemistry technique, we characterized KA1 protein localization in human brain and performed a genotype-protein expression correlation study. KA1 was expressed in specific populations of neuronal cells in the cerebellum and all layers of the frontal and parahippocampal cortices. In the hippocampus, strong KA1 expression was observed in the stratum pyramidale and stratum lucidum of CA3 and CA2, in cell processes in CA1, in the neuropil of the CA4 region, in polymorphic cells including mossy fiber neurons in the hilus, and dentate gyrus (DG) granule cells. Mean counts of KA1 positive DG granule cells, hippocampal CA3 pyramidal cells, and layer 1 of the frontal cortex were significantly increased in subjects with the deletion allele (P = 0.0005, 0.018, and 0.0058, respectively) compared to subjects homozygous for the insertion. Neuronal expression levels in all regions quantified were higher in the deletion group. These results support our hypothesis that the deletion allele affords protection against bipolar disorder through increased KA1 protein abundance in neuronal cells. Biological mechanisms which may contribute to this protective effect include KA1 involvement in adult hippocampal neurogenesis, HPA axis activation, or plasticity processes affecting neuronal circuitry.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2011; 159B(1):21-9. · 3.70 Impact Factor -
Article: Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge.
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ABSTRACT: Apolipoprotein E (APOE)-ɛ4 is associated with a deleterious outcome after ischemic brain injury, which may involve abnormal regulation of mitochondrial function. We have assessed the mitochondrial proteomic response of APOE-ɛ3 and APOE-ɛ4 transgenic mice to transient global ischemic injury in the hippocampus. A genotype-dependent increase in ApoE levels in mitochondria was observed after ischemia, with APOE-ɛ4 mice showing significantly greater increases than APOE-ɛ3 mice. Quantitative analysis of the mitochondria-enriched fractions was performed using liquid-chromatography mass spectrometry coupled to label-free analysis. Of the 1,067 identified proteins, 274 were mitochondria associated. Mitochondrial protein expression was significantly different between genotypes under basal conditions as well as in response to global ischemia. A total of 12 mitochondrial proteins (including respiratory chain proteins NDUFA11, NDUFS3, NDUF5B, ATP5J, as well as ETFA, CYB5B, ATP6V1A, HSPA1B, OXR1, GLUL, IARS2, and PHYHIPL) were significantly altered with respect to genotype, global ischemia, or their interaction (P<0.01). A compelling interactome, created using proteins found to be significantly modulated by global ischemia (P<0.05), involved proteins that regulate energy production and oxidative stress. Thus, APOE genotype has a differential effect on the mitochondrial protein expression in the absence and presence of an injury, which may underlie the differing genotype susceptibility.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2011; 32(1):164-76. · 5.46 Impact Factor -
Article: Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challengeJCBFMOpen
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ABSTRACT: Apolipoprotein E (APOE)-ε4 is associated with a deleterious outcome after ischemic brain injury, which may involve abnormal regulation of mitochondrial function. We have assessed the mitochondrial proteomic response of APOE-ε3 and APOE-ε4 transgenic mice to transient global ischemic injury in the hippocampus. A genotype-dependent increase in ApoE levels in mitochondria was observed after ischemia, with APOE-ε4 mice showing significantly greater increases than APOE-ε3 mice. Quantitative analysis of the mitochondria-enriched fractions was performed using liquid-chromatography mass spectrometry coupled to label-free analysis. Of the 1,067 identified proteins, 274 were mitochondria associated. Mitochondrial protein expression was significantly different between genotypes under basal conditions as well as in response to global ischemia. A total of 12 mitochondrial proteins (including respiratory chain proteins NDUFA11, NDUFS3, NDUF5B, ATP5J, as well as ETFA, CYB5B, ATP6V1A, HSPA1B, OXR1, GLUL, IARS2, and PHYHIPL) were significantly altered with respect to genotype, global ischemia, or their interaction (P<0.01). A compelling interactome, created using proteins found to be significantly modulated by global ischemia (P<0.05), involved proteins that regulate energy production and oxidative stress. Thus, APOE genotype has a differential effect on the mitochondrial protein expression in the absence and presence of an injury, which may underlie the differing genotype susceptibility.Keywords: apolipoprotein E; ischemia; mitochondria; proteomicsJournal of Cerebral Blood Flow & Metabolism 08/2011; 32(1):164-176. · 5.01 Impact Factor -
Article: Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria.
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ABSTRACT: Several independent studies have identified Disrupted In Schizophrenia 1 (DISC1) as a potential susceptibility factor in the pathogenesis of schizophrenia and severe recurrent major depression. To identify potential mechanisms by which DISC1 may influence development of psychiatric illness, we investigated the cellular consequences of recombinant DISC1 expression in COS-7 cells. We show that the N-terminal head domain is sufficient for DISC1 mitochondrial and nuclear targeting, while sequence from the C-terminus facilitates centrosomal association. Loss of C-terminal sequence alters DISC1 subcellular distribution, significantly increasing nuclear localization. DISC1 over-expression produces striking mitochondrial reorganization in some cells, with formation of mitochondrial ring-like structures, indicating a potential involvement of DISC1 in mitochondrial fusion and/or fission.Molecular and Cellular Neuroscience 01/2006; 30(4):477-84. · 3.66 Impact Factor -
Article: DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.
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ABSTRACT: The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.Science 12/2005; 310(5751):1187-91. · 31.20 Impact Factor
