The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins

Harrison, Paul J.; Heath, Paul R.; Eastwood, Sharon L.; Burnet, Philip W.J.; McDonald, B.; Pearson, R.C.A.

doi:10.1016/0304-3940(95)12102-a

Cited by 332 publications

(256 citation statements)

References 21 publications

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“…Thus, it cannot be assumed that because one particular protein, mRNA, etc is stable, all are stable during a certain PMI. In addition to PMI and storage temperature, other factors such as agonal state at death (Bowen et al, 1976;Butterworth et al, 1983;Harrison et al, 1991;Lewis and Akil, 1997;Perry et al, 1977aPerry et al, , 1982Spokes, 1979;Yates et al, 1990), pH (generally related to agonal state) (Barton et al, 1993;Eastwood and Harrison, 2000;Harrison et al, 1995;Johnston et al, 1997;Kingsbury et al, 1995), freezing time (Roytta et al, 1980), and time or season of death (Bucht et al, 1981;Carlsson et al, 1980; Perry et al, 1977a-d), among many others, have been found to influence the degradationFor levelFof biological products in postmortem brain specimens. Thus, it remains critical to ascertain the post-mortem stability, and the stability under other conditions, of the biological product.…”

Section: Discussionmentioning

confidence: 99%

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Gould

Yuan

et al. 2002

Neuropsychopharmacol

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Post-mortem brain tissue provides a unique opportunity to uncover the genes or proteins involved in the pathophysiology of neuropsychiatric disorders. Protein phosphorylation is a common protein modification within intracellular signaling pathways that affects the distribution and function of protein, and has been hypothesized to be of major importance in both the pathophysiology and treatment of major neuropsychiatric disorders. Thus, we were interested in ascertaining the stability of the phosphorylated forms of proteins that are involved in cellular signaling. Antibodies against phospho-tyrosine, phospho-threonine, and phospho-PKA substrates were used to examine the PMI effects on the general amounts of proteins in their phosphorylated form. Phospho-specific antibodies for ERK, JNK, RSK, CREB, and ATF-2 were used to test the effects of PMI on specific proteins whose functioning are known to be regulated markedly by phosphorylation. We found that PMI rapidly decreased the levels of proteins in their phosphorylated states and also decreased the total levels of certain proteins. The PMI effects were observed in the samples stored at both 41C and room temperature, in both frontal cortex and hippocampus. Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI.

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Section: Discussionmentioning

confidence: 99%

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Gould

Yuan

et al. 2002

Neuropsychopharmacol

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“…[56][57][58][59] Correlation analysis showed no association between any of the NMDA receptor subunits and age with the exception of NR2C in DLPFC (r = 0.46, P = 0.03). In the ACC, only NR2B (r = 0.46, P = 0.04) was significantly associated with PMI.…”

Section: Resultsmentioning

confidence: 91%

“…57,60,61 Correlation analysis showed a significant association between PSD-93 and age in ACC (r = 0.38, Pvalue = 0.000009). Expression of PSD-93, SAP102 and NF-L were significantly associated with PMI in DLPFC (r = 0.32, P = 0.0008; r = 0.45, P = 0.000001; r = 0.38, P = 0.00008) and NF-L in ACC (r = 0.30; P = 0.0003).…”

Section: Resultsmentioning

confidence: 96%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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“…The pH of the brain was measured in the cerebellum in all cases as described by Harrison et al (1995).…”

Section: Subjectsmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins

Cited by 332 publications

References 21 publications

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

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