59 results on '"Perreau VM"'
Search Results
2. Melatonin treatment in old mice enables a more youthful response to LPS in the brain
- Author
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Bondy, SC, Perreau, VM, Cotman, CW, Sharman, KZ, and Sharman, EH
- Published
- 2007
3. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci
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Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, Sandbrink R, Pohl C, Edan G, Kappos L, Miller D, Montalbán X, Polman CH, Freedman MS, Hartung HP, Arnason BGW, COMI , GIANCARLO, Cook S, FILIPPI , MASSIMO, Goodin DS, Jeffery D, O'Connor P, Ebers GC, Langdon D, Reder AT, Traboulsee A, Zipp F, Schimrigk J, Hillert J, Bahlo M, Booth DR, BroadleyS, Brown MA, Browning BL, Browning SR, Butzkueven H, Carroll WM, Chapman C, Foote SJ, Griffiths L, Kermode AG, Kilpatrick TJ, Lechner Scott J, Marriott M, Mason D, Moscato P, Heard RN, Pender MP, Perreau VM, Perera D, Rubio JP, Scott RJ, Slee M, Stankovich J, Stewart GJ, Taylor BV, Tubridy N, Willoughby E, Wiley J, Matthews P, Boneschi F, Compston A, Haines J, Hauser SL, McCauley J, Ivinson A, Oksenberg JR, Pericak Vance M, Sawcer SJ, De Jager PL, Hafler DA, de Bakker PIW, the BSP MS Genetics working group, the steering committees of studies evaluating IFNb 1b, a. CCR1 antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium, Neurology, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, Patsopoulos, Na, Esposito, F, Reischl, J, Lehr, S, Bauer, D, Heubach, J, Sandbrink, R, Pohl, C, Edan, G, Kappos, L, Miller, D, Montalbán, X, Polman, Ch, Freedman, M, Hartung, Hp, Arnason, Bgw, Comi, Giancarlo, Cook, S, Filippi, Massimo, Goodin, D, Jeffery, D, O'Connor, P, Ebers, Gc, Langdon, D, Reder, At, Traboulsee, A, Zipp, F, Schimrigk, J, Hillert, J, Bahlo, M, Booth, Dr, Broadleys, Brown, Ma, Browning, Bl, Browning, Sr, Butzkueven, H, Carroll, Wm, Chapman, C, Foote, Sj, Griffiths, L, Kermode, Ag, Kilpatrick, Tj, Lechner Scott, J, Marriott, M, Mason, D, Moscato, P, Heard, Rn, Pender, Mp, Perreau, Vm, Perera, D, Rubio, Jp, Scott, Rj, Slee, M, Stankovich, J, Stewart, Gj, Taylor, Bv, Tubridy, N, Willoughby, E, Wiley, J, Matthews, P, Boneschi, F, Compston, A, Haines, J, Hauser, Sl, Mccauley, J, Ivinson, A, Oksenberg, Jr, Pericak Vance, M, Sawcer, Sj, De Jager, Pl, Hafler, Da, de Bakker, Piw, the BSP MS Genetics working, Group, the steering committees of studies evaluating IFNb, 1b, A., CCR1 antagonist, Anzgene, Consortium, Genemsa, and International Multiple Sclerosis Genetics, Consortium
- Subjects
Male ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Single-nucleotide polymorphism ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Article ,Major Histocompatibility Complex ,Animals ,Humans ,Genetic Predisposition to Disease ,International HapMap Project ,Genetic association ,25-Hydroxyvitamin D3 1-alpha-Hydroxylase ,Genetics ,T-Lymphocytes, Helper-Inducer ,Genetic architecture ,Neurology ,Mutation ,Expression quantitative trait loci ,Female ,Disease Susceptibility ,Neurology (clinical) ,Imputation (genetics) - Abstract
OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
- Published
- 2016
4. Short-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington's Disease Transgenic Mice
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Zajac, MS, Renoir, T, Perreau, VM, Li, S, Adams, W, van den Buuse, M, Hannan, AJ, Zajac, MS, Renoir, T, Perreau, VM, Li, S, Adams, W, van den Buuse, M, and Hannan, AJ
- Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability
- Published
- 2018
5. Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety
- Author
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Short, AK, Yeshurun, S, Powell, R, Perreau, VM, Fox, A, Kim, JH, Pang, TY, Hannan, AJ, Short, AK, Yeshurun, S, Powell, R, Perreau, VM, Fox, A, Kim, JH, Pang, TY, and Hannan, AJ
- Published
- 2017
6. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring
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Short, AK, Fennell, KA, Perreau, VM, Fox, A, O'bryan, MK, Kim, JH, Bredy, TW, Pang, TY, Hannan, AJ, Short, AK, Fennell, KA, Perreau, VM, Fox, A, O'bryan, MK, Kim, JH, Bredy, TW, Pang, TY, and Hannan, AJ
- Published
- 2016
7. Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium
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Horvay, K, Jarde, T, Casagranda, F, Perreau, VM, Haigh, K, Nefzger, CM, Akhtar, R, Gridley, T, Berx, G, Haigh, JJ, Barker, N, Polo, JM, Hime, GR, Abud, HE, Horvay, K, Jarde, T, Casagranda, F, Perreau, VM, Haigh, K, Nefzger, CM, Akhtar, R, Gridley, T, Berx, G, Haigh, JJ, Barker, N, Polo, JM, Hime, GR, and Abud, HE
- Abstract
Snail family members regulate epithelial-to-mesenchymal transition (EMT) during invasion of intestinal tumours, but their role in normal intestinal homeostasis is unknown. Studies in breast and skin epithelia indicate that Snail proteins promote an undifferentiated state. Here, we demonstrate that conditional knockout of Snai1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells and bias towards differentiation of secretory lineages. In vitro organoid cultures derived from Snai1 conditional knockout mice also undergo apoptosis when Snai1 is deleted. Conversely, ectopic expression of Snai1 in the intestinal epithelium in vivo results in the expansion of the crypt base columnar cell pool and a decrease in secretory enteroendocrine and Paneth cells. Following conditional deletion of Snai1, the intestinal epithelium fails to produce a proliferative response following radiation-induced damage indicating a fundamental requirement for Snai1 in epithelial regeneration. These results demonstrate that Snai1 is required for regulation of lineage choice, maintenance of CBC stem cells and regeneration of the intestinal epithelium following damage.
- Published
- 2015
8. Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis
- Author
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Capurro, A, Bodea, L-G, Schaefer, P, Luthi-Carter, R, Perreau, VM, Capurro, A, Bodea, L-G, Schaefer, P, Luthi-Carter, R, and Perreau, VM
- Abstract
The characterization of molecular changes in diseased tissues gives insight into pathophysiological mechanisms and is important for therapeutic development. Genome-wide gene expression analysis has proven valuable for identifying biological processes in neurodegenerative diseases using post mortem human brain tissue and numerous datasets are publically available. However, many studies utilize heterogeneous tissue samples consisting of multiple cell types, all of which contribute to global gene expression values, confounding biological interpretation of the data. In particular, changes in numbers of neuronal and glial cells occurring in neurodegeneration confound transcriptomic analyses, particularly in human brain tissues where sample availability and controls are limited. To identify cell specific gene expression changes in neurodegenerative disease, we have applied our recently published computational deconvolution method, population specific expression analysis (PSEA). PSEA estimates cell-type-specific expression values using reference expression measures, which in the case of brain tissue comprises mRNAs with cell-type-specific expression in neurons, astrocytes, oligodendrocytes and microglia. As an exercise in PSEA implementation and hypothesis development regarding neurodegenerative diseases, we applied PSEA to Parkinson's and Huntington's disease (PD, HD) datasets. Genes identified as differentially expressed in substantia nigra pars compacta neurons by PSEA were validated using external laser capture microdissection data. Network analysis and Annotation Clustering (DAVID) identified molecular processes implicated by differential gene expression in specific cell types. The results of these analyses provided new insights into the implementation of PSEA in brain tissues and additional refinement of molecular signatures in human HD and PD.
- Published
- 2015
9. Microarray profiling to analyze the effect of Snai1 loss in mouse intestinal epithelium
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Hime, GR, Horvay, K, Jarde, T, Casagranda, F, Perreau, VM, Abud, HE, Hime, GR, Horvay, K, Jarde, T, Casagranda, F, Perreau, VM, and Abud, HE
- Abstract
Epithelial stem cells from a variety of tissues have been shown to express genes linked to mesenchymal cell states. The Snail family of transcriptional factors has long been regarded as a marker of mesenchymal cells, however recent studies have indicated an involvement in regulation of epithelial stem cell populations. Snai1 is expressed in the stem cell population found at the base of the mouse small intestinal crypt that is responsible for generating all differentiated cell types of the intestinal epithelium. We utilized an inducible Cre recombinase approach in the intestinal epithelium combined with a conditional floxed Snai1 allele to induce knockout of gene function in the stem cell population. Loss of Snai1 resulted in loss of crypt base columnar cells and a failure to induce a proliferative response following radiation damage. We induced Snai1 loss in cultured organoids that had been derived from epithelial cells and compared gene expression to organoids with functional Snai1. Here we describe in detail the methods for generation of knockout organoids and analysis of microarray data that has been deposited in Gene Expression Omnibus (GEO):GSE65005.
- Published
- 2015
10. Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution
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Gresle, MM, Schulz, K, Jonas, A, Perreau, VM, Cipriani, T, Baxter, AG, Miranda-Hernandez, S, Field, J, Jokubaitis, VG, Cherny, R, Volitakis, I, David, S, Kilpatrick, TJ, Butzkueven, H, Gresle, MM, Schulz, K, Jonas, A, Perreau, VM, Cipriani, T, Baxter, AG, Miranda-Hernandez, S, Field, J, Jokubaitis, VG, Cherny, R, Volitakis, I, David, S, Kilpatrick, TJ, and Butzkueven, H
- Abstract
We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.
- Published
- 2014
11. MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes
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ffrench-Constant, C, Bujalka, H, Koenning, M, Jackson, S, Perreau, VM, Pope, B, Hay, CM, Mitew, S, Hill, AF, Lu, QR, Wegner, M, Srinivasan, R, Svaren, J, Willingham, M, Barres, BA, Emery, B, ffrench-Constant, C, Bujalka, H, Koenning, M, Jackson, S, Perreau, VM, Pope, B, Hay, CM, Mitew, S, Hill, AF, Lu, QR, Wegner, M, Srinivasan, R, Svaren, J, Willingham, M, Barres, BA, and Emery, B
- Abstract
The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domain related to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocyte differentiation and CNS myelination.
- Published
- 2013
12. Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis
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Jokubaitis, VG, Gresle, MM, Kemper, DA, Doherty, W, Perreau, VM, Cipriani, TL, Jonas, A, Shaw, G, Kuhlmann, T, Kilpatrick, TJ, Butzkueven, H, Jokubaitis, VG, Gresle, MM, Kemper, DA, Doherty, W, Perreau, VM, Cipriani, TL, Jonas, A, Shaw, G, Kuhlmann, T, Kilpatrick, TJ, and Butzkueven, H
- Abstract
BACKGROUND: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system. RESULTS: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury. CONCLUSIONS: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
- Published
- 2013
13. Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis
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Toland, AE, Lin, R, Charlesworth, J, Stankovich, J, Perreau, VM, Brown, MA, Taylor, BV, Toland, AE, Lin, R, Charlesworth, J, Stankovich, J, Perreau, VM, Brown, MA, and Taylor, BV
- Abstract
Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.
- Published
- 2013
14. Differential Gene Expression in the EphA4 Knockout Spinal Cord and Analysis of the Inflammatory Response Following Spinal Cord Injury
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Langmann, T, Munro, KM, Perreau, VM, Turnley, AM, Langmann, T, Munro, KM, Perreau, VM, and Turnley, AM
- Abstract
Mice lacking the axon guidance molecule EphA4 have been shown to exhibit extensive axonal regeneration and functional recovery following spinal cord injury. To assess mechanisms by which EphA4 may modify the response to neural injury a microarray was performed on spinal cord tissue from mice with spinal cord injury and sham injured controls. RNA was purified from spinal cords of adult EphA4 knockout and wild-type mice four days following lumbar spinal cord hemisection or laminectomy only and was hybridised to Affymetrix All-Exon Array 1.0 GeneChips™. While subsequent analyses indicated that several pathways were altered in EphA4 knockout mice, of particular interest was the attenuated expression of a number of inflammatory genes, including Arginase 1, expression of which was lower in injured EphA4 knockout compared to wild-type mice. Immunohistological analyses of different cellular components of the immune response were then performed in injured EphA4 knockout and wildtype spinal cords. While numbers of infiltrating CD3+ T cells were low in the hemisection model, a robust CD11b+ macrophage/microglial response was observed post-injury. There was no difference in the overall number or spread of macrophages/activated microglia in injured EphA4 knockout compared to wild-type spinal cords at 2, 4 or 14 days post-injury, however a lower proportion of Arginase-1 immunoreactive macrophages/activated microglia was observed in EphA4 knockout spinal cords at 4 days post-injury. Subtle alterations in the neuroinflammatory response in injured EphA4 knockout spinal cords may contribute to the regeneration and recovery observed in these mice following injury.
- Published
- 2012
15. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20
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Bahlo, M, Booth, DR, Broadley, SA, Brown, MA, Foote, SJ, Griffiths, LR, Kilpatrick, TJ, Lechner-Scott, J, Moscato, P, Perreau, VM, Rubio, JP, Scott, RJ, Stankovich, J, Stewart, GJ, Taylor, BV, Wiley, J, Clarke, G, Cox, MB, Csurhes, PA, Danoy, P, Drysdale, K, Field, J, Greer, JM, Guru, P, Hadler, J, McMorran, BJ, Jensen, CJ, Johnson, LJ, McCallum, R, Merriman, M, Merriman, T, Pryce, K, Tajouri, L, Wilkins, EJ, Browning, BL, Browning, SR, Perera, D, Butzkueven, H, Carroll, WM, Chapman, C, Kermode, AG, Marriott, M, Mason, D, Heard, RN, Pender, MP, Slee, M, Tubridy, N, Willoughby, E, Bahlo, M, Booth, DR, Broadley, SA, Brown, MA, Foote, SJ, Griffiths, LR, Kilpatrick, TJ, Lechner-Scott, J, Moscato, P, Perreau, VM, Rubio, JP, Scott, RJ, Stankovich, J, Stewart, GJ, Taylor, BV, Wiley, J, Clarke, G, Cox, MB, Csurhes, PA, Danoy, P, Drysdale, K, Field, J, Greer, JM, Guru, P, Hadler, J, McMorran, BJ, Jensen, CJ, Johnson, LJ, McCallum, R, Merriman, M, Merriman, T, Pryce, K, Tajouri, L, Wilkins, EJ, Browning, BL, Browning, SR, Perera, D, Butzkueven, H, Carroll, WM, Chapman, C, Kermode, AG, Marriott, M, Mason, D, Heard, RN, Pender, MP, Slee, M, Tubridy, N, and Willoughby, E
- Abstract
To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
- Published
- 2009
16. Acetylcholine Muscarinic M 4 Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents.
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Walker LC, Berizzi AE, Chen NA, Rueda P, Perreau VM, Huckstep K, Srisontiyakul J, Govitrapong P, Xiaojian J, Lindsley CW, Jones CK, Riddy DM, Christopoulos A, Langmead CJ, and Lawrence AJ
- Subjects
- Acetylcholine, Animals, Cholinergic Agents, Humans, Rats, Rodentia, Alcoholism drug therapy, Alcoholism genetics, Receptor, Muscarinic M4 genetics
- Abstract
Background: Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function., Methods: We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate-putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target., Results: We found that G protein-coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M
4 muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M4 mAChR, specifically on dopamine D1 receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M4 mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking., Conclusions: Collectively, these results identify the M4 mAChR as a potential therapeutic target for the treatment of AUD and the D1 receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M4 mAChR in relation to alcohol consumption and seeking., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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17. Inflammation in Traumatic Brain Injury: Roles for Toxic A1 Astrocytes and Microglial-Astrocytic Crosstalk.
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Clark DPQ, Perreau VM, Shultz SR, Brady RD, Lei E, Dixit S, Taylor JM, Beart PM, and Boon WC
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- Animals, Astrocytes pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Complement C3 metabolism, Equidae, Glial Fibrillary Acidic Protein metabolism, Goats, Male, Mice, Microglia pathology, Rabbits, Rats, Sprague-Dawley, Astrocytes metabolism, Brain Injuries, Traumatic metabolism, Inflammation metabolism, Microglia metabolism
- Abstract
Traumatic brain injury triggers neuroinflammation that may contribute to progressive neurodegeneration. We investigated patterns of recruitment of astrocytes and microglia to inflammation after brain trauma by firstly characterising expression profiles over time of marker genes following TBI, and secondly by monitoring glial morphologies reflecting inflammatory responses in a rat model of traumatic brain injury (i.e. the lateral fluid percussion injury). Gene expression profiles revealed early elevation of expression of astrocytic marker glial fibrillary acidic protein relative to microglial marker allograft inflammatory factor 1 (also known as ionized calcium-binding adapter molecule 1). Adult rat brains collected at day 7 after injury were processed for immunohistochemistry with allograft inflammatory factor 1, glial fibrillary acidic protein and complement C3 (marker of bad/disruptive astrocytic A1 phenotype). Astrocytes positive for glial fibrillary acidic protein and complement C3 were significant increased in the injured cortex and displayed more complex patterns of arbourisation with significantly increased bifurcations. Our observations suggested that traumatic brain injury changed the phenotype of microglia from a ramified appearance with long, thin, highly branched processes to a swollen amoeboid shape in the injured cortex. These findings suggest differential glial activation with astrocytes likely undergoing strategic changes in morphology and function. Whilst a detailed analysis is needed of temporal patterns of glial activation, ours is the first evidence of a role for the bad/disruptive astrocytic A1 phenotype in an open head model of traumatic brain injury.
- Published
- 2019
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18. Short-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington's Disease Transgenic Mice.
- Author
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Zajac MS, Renoir T, Perreau VM, Li S, Adams W, van den Buuse M, and Hannan AJ
- Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT
1A , 5-HT1B , 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.- Published
- 2018
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19. Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety.
- Author
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Short AK, Yeshurun S, Powell R, Perreau VM, Fox A, Kim JH, Pang TY, and Hannan AJ
- Subjects
- Animals, Anxiety psychology, Depression genetics, Depression psychology, Environmental Exposure adverse effects, Female, Gene Expression Regulation, Hypothalamo-Hypophyseal System physiopathology, Male, Mice, Mice, Inbred C57BL, Phenotype, Pituitary-Adrenal System physiopathology, RNA, Small Untranslated, Anxiety genetics, Fear psychology, Infectious Disease Transmission, Vertical veterinary, MicroRNAs genetics, Physical Conditioning, Animal adverse effects, Spermatozoa metabolism
- Abstract
There is growing evidence that the preconceptual lifestyle and other environmental exposures of a father can significantly alter the physiological and behavioral phenotypes of their children. We and others have shown that paternal preconception stress, regardless of whether the stress was experienced during early-life or adulthood, results in offspring with altered anxiety and depression-related behaviors, attributed to hypothalamic-pituitary-adrenal axis dysregulation. The transgenerational response to paternal preconceptual stress is believed to be mediated by sperm-borne small noncoding RNAs, specifically microRNAs. As physical activity confers physical and mental health benefits for the individual, we used a model of voluntary wheel-running and investigated the transgenerational response to paternal exercise. We found that male offspring of runners had suppressed reinstatement of juvenile fear memory, and reduced anxiety in the light-dark apparatus during adulthood. No changes in these affective behaviors were observed in female offspring. We were surprised to find that running had a limited impact on sperm-borne microRNAs. The levels of three unique microRNAs (miR-19b, miR-455 and miR-133a) were found to be altered in the sperm of runners. In addition, we discovered that the levels of two species of tRNA-derived RNAs (tDRs)-tRNA-Gly and tRNA-Pro-were also altered by running. Taken together, we believe this is the first evidence that paternal exercise is associated with an anxiolytic behavioral phenotype of male offspring and altered levels of small noncoding RNAs in sperm. These small noncoding RNAs are known to have an impact on post-transcriptional gene regulation and can thus change the developmental trajectory of offspring brains and associated affective behaviors.
- Published
- 2017
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20. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring.
- Author
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Short AK, Fennell KA, Perreau VM, Fox A, O'Bryan MK, Kim JH, Bredy TW, Pang TY, and Hannan AJ
- Subjects
- Animals, Anxiety physiopathology, Brain-Derived Neurotrophic Factor genetics, Depression physiopathology, Exons, Fear drug effects, Fear physiology, Female, Gene Expression genetics, Gene Expression physiology, Insulin-Like Growth Factor II genetics, Male, Maze Learning drug effects, Maze Learning physiology, Mice, Inbred C57BL, MicroRNAs genetics, Pregnancy, Sex Factors, Anxiety genetics, Corticosterone pharmacology, Depression genetics, Hypothalamo-Hypophyseal System physiopathology, Paternal Exposure, Phenotype, Pituitary-Adrenal System physiopathology, RNA, Small Untranslated genetics, Spermatozoa drug effects, Spermatozoa metabolism
- Abstract
Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic-pituitary-adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light-dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.
- Published
- 2016
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21. Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes.
- Author
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Xu H, Perreau VM, Dent KA, Bush AI, Finkelstein DI, and Adlard PA
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Astrocytes drug effects, Blotting, Western, Cell Survival drug effects, Cell Survival physiology, Cells, Cultured, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Copper metabolism, Ferritins metabolism, Immunohistochemistry, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Inbred C57BL, Neurons drug effects, Polymerase Chain Reaction, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Receptors, LDL metabolism, Tumor Suppressor Proteins metabolism, Zinc metabolism, Apolipoproteins E metabolism, Astrocytes metabolism, Iron metabolism, Neurons metabolism
- Abstract
Background: There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer's disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored., Objective: This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes., Methods: Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE., Results: We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1., Conclusion: Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.
- Published
- 2016
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22. Microarray profiling to analyze the effect of Snai1 loss in mouse intestinal epithelium.
- Author
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Hime GR, Horvay K, Jardé T, Casagranda F, Perreau VM, and Abud HE
- Abstract
Epithelial stem cells from a variety of tissues have been shown to express genes linked to mesenchymal cell states. The Snail family of transcriptional factors has long been regarded as a marker of mesenchymal cells, however recent studies have indicated an involvement in regulation of epithelial stem cell populations. Snai1 is expressed in the stem cell population found at the base of the mouse small intestinal crypt that is responsible for generating all differentiated cell types of the intestinal epithelium. We utilized an inducible Cre recombinase approach in the intestinal epithelium combined with a conditional floxed Snai1 allele to induce knockout of gene function in the stem cell population. Loss of Snai1 resulted in loss of crypt base columnar cells and a failure to induce a proliferative response following radiation damage. We induced Snai1 loss in cultured organoids that had been derived from epithelial cells and compared gene expression to organoids with functional Snai1. Here we describe in detail the methods for generation of knockout organoids and analysis of microarray data that has been deposited in Gene Expression Omnibus (GEO):GSE65005.
- Published
- 2015
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23. Galanin is an autocrine myelin and oligodendrocyte trophic signal induced by leukemia inhibitory factor.
- Author
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Gresle MM, Butzkueven H, Perreau VM, Jonas A, Xiao J, Thiem S, Holmes FE, Doherty W, Soo PY, Binder MD, Akkermann R, Jokubaitis VG, Cate HS, Marriott MP, Gundlach AL, Wynick D, and Kilpatrick TJ
- Subjects
- Animals, Astrocytes pathology, Astrocytes physiology, Brain pathology, Brain physiopathology, Cell Survival physiology, Cells, Cultured, Cuprizone, Demyelinating Diseases pathology, Demyelinating Diseases physiopathology, Disease Models, Animal, Galanin genetics, Gene Expression, MAP Kinase Signaling System physiology, Mice, Inbred C57BL, Mice, Knockout, Myelin Sheath pathology, Neural Stem Cells pathology, Neural Stem Cells physiology, Oligodendroglia pathology, Optic Nerve pathology, Optic Nerve physiology, RNA, Messenger metabolism, Rats, Sprague-Dawley, Galanin metabolism, Leukemia Inhibitory Factor metabolism, Myelin Sheath physiology, Oligodendroglia physiology
- Abstract
In order to further investigate the molecular mechanisms that regulate oligodendrocyte (OC) survival, we utilized microarrays to characterize changes in OC gene expression after exposure to the cytokines neurotrophin3, insulin, or leukemia inhibitory factor (LIF) in vitro. We identified and validated the induction and secretion of the neuropeptide galanin in OCs, specifically in response to LIF. We next established that galanin is an OC survival factor and showed that autocrine or paracrine galanin secretion mediates LIF-induced OC survival in vitro. We also revealed that galanin is up-regulated in OCs in the cuprizone model of central demyelination, and that oligodendroglial galanin expression is significantly regulated by endogenous LIF in this context. We also showed that knock-out of galanin reduces OC survival and exacerbates callosal demyelination in the cuprizone model. These findings suggest a potential role for the use of galanin agonists in the treatment of human demyelinating diseases., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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24. Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium.
- Author
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Horvay K, Jardé T, Casagranda F, Perreau VM, Haigh K, Nefzger CM, Akhtar R, Gridley T, Berx G, Haigh JJ, Barker N, Polo JM, Hime GR, and Abud HE
- Subjects
- Animals, Apoptosis genetics, Apoptosis physiology, Cell Differentiation genetics, Cell Differentiation physiology, Cell Lineage, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Mice, Mice, Knockout, Signal Transduction genetics, Signal Transduction physiology, Snail Family Transcription Factors, Transcription Factors genetics, Intestinal Mucosa metabolism, Intestines cytology, Transcription Factors metabolism
- Abstract
Snail family members regulate epithelial-to-mesenchymal transition (EMT) during invasion of intestinal tumours, but their role in normal intestinal homeostasis is unknown. Studies in breast and skin epithelia indicate that Snail proteins promote an undifferentiated state. Here, we demonstrate that conditional knockout of Snai1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells and bias towards differentiation of secretory lineages. In vitro organoid cultures derived from Snai1 conditional knockout mice also undergo apoptosis when Snai1 is deleted. Conversely, ectopic expression of Snai1 in the intestinal epithelium in vivo results in the expansion of the crypt base columnar cell pool and a decrease in secretory enteroendocrine and Paneth cells. Following conditional deletion of Snai1, the intestinal epithelium fails to produce a proliferative response following radiation-induced damage indicating a fundamental requirement for Snai1 in epithelial regeneration. These results demonstrate that Snai1 is required for regulation of lineage choice, maintenance of CBC stem cells and regeneration of the intestinal epithelium following damage., (© 2015 The Authors.)
- Published
- 2015
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25. Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis.
- Author
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Capurro A, Bodea LG, Schaefer P, Luthi-Carter R, and Perreau VM
- Abstract
The characterization of molecular changes in diseased tissues gives insight into pathophysiological mechanisms and is important for therapeutic development. Genome-wide gene expression analysis has proven valuable for identifying biological processes in neurodegenerative diseases using post mortem human brain tissue and numerous datasets are publically available. However, many studies utilize heterogeneous tissue samples consisting of multiple cell types, all of which contribute to global gene expression values, confounding biological interpretation of the data. In particular, changes in numbers of neuronal and glial cells occurring in neurodegeneration confound transcriptomic analyses, particularly in human brain tissues where sample availability and controls are limited. To identify cell specific gene expression changes in neurodegenerative disease, we have applied our recently published computational deconvolution method, population specific expression analysis (PSEA). PSEA estimates cell-type-specific expression values using reference expression measures, which in the case of brain tissue comprises mRNAs with cell-type-specific expression in neurons, astrocytes, oligodendrocytes and microglia. As an exercise in PSEA implementation and hypothesis development regarding neurodegenerative diseases, we applied PSEA to Parkinson's and Huntington's disease (PD, HD) datasets. Genes identified as differentially expressed in substantia nigra pars compacta neurons by PSEA were validated using external laser capture microdissection data. Network analysis and Annotation Clustering (DAVID) identified molecular processes implicated by differential gene expression in specific cell types. The results of these analyses provided new insights into the implementation of PSEA in brain tissues and additional refinement of molecular signatures in human HD and PD.
- Published
- 2015
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26. Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution.
- Author
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Gresle MM, Schulz K, Jonas A, Perreau VM, Cipriani T, Baxter AG, Miranda-Hernandez S, Field J, Jokubaitis VG, Cherny R, Volitakis I, David S, Kilpatrick TJ, and Butzkueven H
- Subjects
- Animals, Blotting, Western, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Spinal Cord pathology, Transcriptome, Ceruloplasmin metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology
- Abstract
We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution., (Copyright © 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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27. Endogenously regulated Dab2 worsens inflammatory injury in experimental autoimmune encephalomyelitis.
- Author
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Jokubaitis VG, Gresle MM, Kemper DA, Doherty W, Perreau VM, Cipriani TL, Jonas A, Shaw G, Kuhlmann T, Kilpatrick TJ, and Butzkueven H
- Subjects
- Adaptor Proteins, Vesicular Transport genetics, Animals, Apoptosis Regulatory Proteins, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Interleukin-1beta metabolism, Macrophages immunology, Male, Mice, Inbred C57BL, Mice, Knockout, Microglia immunology, Multiple Sclerosis metabolism, Neuroimmunomodulation physiology, Nitric Oxide Synthase Type II metabolism, Severity of Illness Index, T-Lymphocytes physiology, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Vesicular Transport metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Multiple Sclerosis immunology, Spinal Cord immunology, Tumor Suppressor Proteins metabolism
- Abstract
Background: Neuroinflammation regulates both disease pathogenesis and repair in multiple sclerosis. In early multiple sclerosis lesion development, neuroinflammation causes demyelination and axonal injury, the likely final common determinant of disability. Here we report the identification of a novel neuroinflammatory mediator, Disabled-2 (Dab2). Dab2 is an intracellular adaptor protein with previously unknown function in the central nervous system., Results: We report that Dab2 is up-regulated in lesional macrophages/microglia in the spinal cord in murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. We demonstrate that dab2 expression is positively correlated with experimental autoimmune encephalomyelitis disease severity during the acute disease phase. Furthermore, dab2-deficient mice have a less severe experimental autoimmune encephalomyelitis disease course and suffer less neuroinflammation and less axonal injury than their wild-type littermates. We demonstrate that dab2 expression is strongly associated with the expression of inducible nitric oxide synthase. We further demonstrate that Dab2 is expressed at the protein level by macrophages in early acute human multiple sclerosis lesions and that this correlates with axonal injury., Conclusions: Together, these results suggest that endogenous Dab2 exacerbates central nervous system inflammation, potentially acting to up-regulate reactive oxygen species expression in macrophages and microglia, and that it is of potential pathogenic relevance in Multiple Sclerosis.
- Published
- 2013
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28. Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
- Author
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Lin R, Charlesworth J, Stankovich J, Perreau VM, Brown MA, and Taylor BV
- Subjects
- Case-Control Studies, Chromosomes, Human, Pair 9, Databases, Genetic, Genetic Variation, Genotype, Haplotypes, Humans, Lod Score, Models, Genetic, Multigene Family, Principal Component Analysis, Zinc Fingers, Chromosome Mapping methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Multiple Sclerosis genetics
- Abstract
Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.
- Published
- 2013
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29. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes.
- Author
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Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, Srinivasan R, Svaren J, Willingham M, Barres BA, and Emery B
- Subjects
- Animals, Cell Line, Cells, Cultured, Chromatin Immunoprecipitation, Gene Expression Regulation genetics, Gene Expression Regulation physiology, Humans, Membrane Proteins genetics, Mice, Mutagenesis, Site-Directed, Myelin Sheath metabolism, Oligodendroglia metabolism, Transcription Factors genetics, Membrane Proteins metabolism, Transcription Factors metabolism
- Abstract
The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domain related to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocyte differentiation and CNS myelination., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2013
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30. Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses.
- Author
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Lau CL, Perreau VM, Chen MJ, Cate HS, Merlo D, Cheung NS, O'Shea RD, and Beart PM
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Animals, Astrocytes cytology, Mice, Mice, Inbred C57BL, Primary Cell Culture, Protein Kinase Inhibitors pharmacology, Transcriptome genetics, rho-Associated Kinases genetics, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, Astrocytes drug effects, Astrocytes enzymology, Gene Expression Profiling methods, Transcriptome drug effects, rho-Associated Kinases antagonists & inhibitors
- Abstract
Inhibitors of Rho kinase (ROCK) have potential for management of neurological disorders by inhibition of glial scarring. Since astrocytes play key roles in brain physiology and pathology, we determined changes in the astrocytic transcriptome produced by the ROCK inhibitor Fasudil to obtain mechanistic insights into its beneficial action during brain injury. Cultured murine astrocytes were treated with Fasudil (100 µM) and morphological analyses revealed rapid stellation by 1 h and time-dependent (2-24 h) dissipation of F-actin-labelled stress fibres. Microarray analyses were performed on RNA and the time-course of global gene profiling (2, 6, 12 and 24 h) provided a comprehensive description of transcriptomic changes. Hierarchical clustering of differentially expressed genes and analysis for over-represented gene ontology groups using the DAVID database focused attention on Fasudil-induced changes to major biological processes regulating cellular shape and motility (actin cytoskeleton, axon guidance, transforming growth factor-β (TGFβ) signalling and tight junctions). Bioinformatic analyses of transcriptomic changes revealed how these biological processes contributed to changes in astrocytic motility and cytoskeletal reorganisation. Here genes associated with extracellular matrix were also involved, but unexpected was a subset of alterations (EAAT2, BDNF, anti-oxidant species, metabolic and signalling genes) indicative of adoption by astrocytes of a pro-survival phenotype. Expression profiles of key changes with Fasudil and another ROCK inhibitor Y27632 were validated by real-time PCR. Although effects of ROCK inhibition have been considered to be primarily cytoskeletal via reduction of glial scarring, we demonstrate additional advantageous actions likely to contribute to their ameliorative actions in brain injury., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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31. Differential gene expression in the EphA4 knockout spinal cord and analysis of the inflammatory response following spinal cord injury.
- Author
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Munro KM, Perreau VM, and Turnley AM
- Subjects
- Animals, Gene Expression, Inflammation metabolism, Inflammation pathology, Lumbar Vertebrae, Mice, Microglia metabolism, Microglia pathology, Nerve Regeneration physiology, Neurons metabolism, Neurons pathology, Receptor, EphA4 metabolism, Recovery of Function, Spinal Cord pathology, Spinal Cord Injuries metabolism, Spinal Cord Injuries pathology, Inflammation genetics, Receptor, EphA4 genetics, Spinal Cord metabolism, Spinal Cord Injuries genetics
- Abstract
Mice lacking the axon guidance molecule EphA4 have been shown to exhibit extensive axonal regeneration and functional recovery following spinal cord injury. To assess mechanisms by which EphA4 may modify the response to neural injury a microarray was performed on spinal cord tissue from mice with spinal cord injury and sham injured controls. RNA was purified from spinal cords of adult EphA4 knockout and wild-type mice four days following lumbar spinal cord hemisection or laminectomy only and was hybridised to Affymetrix All-Exon Array 1.0 GeneChips™. While subsequent analyses indicated that several pathways were altered in EphA4 knockout mice, of particular interest was the attenuated expression of a number of inflammatory genes, including Arginase 1, expression of which was lower in injured EphA4 knockout compared to wild-type mice. Immunohistological analyses of different cellular components of the immune response were then performed in injured EphA4 knockout and wildtype spinal cords. While numbers of infiltrating CD3+ T cells were low in the hemisection model, a robust CD11b+ macrophage/microglial response was observed post-injury. There was no difference in the overall number or spread of macrophages/activated microglia in injured EphA4 knockout compared to wild-type spinal cords at 2, 4 or 14 days post-injury, however a lower proportion of Arginase-1 immunoreactive macrophages/activated microglia was observed in EphA4 knockout spinal cords at 4 days post-injury. Subtle alterations in the neuroinflammatory response in injured EphA4 knockout spinal cords may contribute to the regeneration and recovery observed in these mice following injury.
- Published
- 2012
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32. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.
- Author
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Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, Sandbrink R, Pohl C, Edan G, Kappos L, Miller D, Montalbán J, Polman CH, Freedman MS, Hartung HP, Arnason BG, Comi G, Cook S, Filippi M, Goodin DS, Jeffery D, O'Connor P, Ebers GC, Langdon D, Reder AT, Traboulsee A, Zipp F, Schimrigk S, Hillert J, Bahlo M, Booth DR, Broadley S, Brown MA, Browning BL, Browning SR, Butzkueven H, Carroll WM, Chapman C, Foote SJ, Griffiths L, Kermode AG, Kilpatrick TJ, Lechner-Scott J, Marriott M, Mason D, Moscato P, Heard RN, Pender MP, Perreau VM, Perera D, Rubio JP, Scott RJ, Slee M, Stankovich J, Stewart GJ, Taylor BV, Tubridy N, Willoughby E, Wiley J, Matthews P, Boneschi FM, Compston A, Haines J, Hauser SL, McCauley J, Ivinson A, Oksenberg JR, Pericak-Vance M, Sawcer SJ, De Jager PL, Hafler DA, and de Bakker PI
- Subjects
- Adolescent, Adult, Child, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Multiple Sclerosis etiology, Odds Ratio, Young Adult, Disease Susceptibility, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci., Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease., Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1)., Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS., (Copyright © 2011 American Neurological Association.)
- Published
- 2011
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33. A potential copper-regulatory role for cytosolic expression of the DNA repair protein XRCC5.
- Author
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Du T, Caragounis A, Parker SJ, Meyerowitz J, La Fontaine S, Kanninen KM, Perreau VM, Crouch PJ, and White AR
- Subjects
- Antigens, Nuclear biosynthesis, Cell Death drug effects, Cell Survival drug effects, Cells, Cultured, Copper pharmacology, Cytosol drug effects, DNA Damage, DNA Helicases biosynthesis, DNA Repair, DNA-Binding Proteins biosynthesis, Dose-Response Relationship, Drug, HeLa Cells, Humans, Ku Autoantigen, Oxidative Stress drug effects, Copper metabolism, Cytosol metabolism, DNA Helicases metabolism
- Abstract
Copper (Cu) has a critical role in the generation of oxidative stress during neurodegeneration and cancer. Reactive oxygen species generated through abnormal elevation or deficiency of Cu can lead to lipid, protein, and DNA damage. Oxidation of DNA can induce strand breaks and is associated with altered cell fate including transformation or death. DNA repair is mediated through the action of the multimeric DNA-PK repair complex. The components of this complex are the Ku autoantigens, XRCC5 and XRCC6 (Ku80 and Ku70, respectively). How this repair complex responds to perturbed Cu homeostasis and Cu-mediated oxidative stress has not been investigated. We previously reported that XRCC5 expression is altered in response to cellular Cu levels, with low Cu inhibiting XRCC5 expression and high Cu levels enhancing expression. In this study we further investigated the interaction between XRCC5 and Cu. We report that cytosolic XRCC5 is increased in response to Cu, but not zinc, iron, or nickel, and the level of cytosolic XRCC5 correlates with protection against oxidative damage to DNA. These observations were made in both HeLa cells and fibroblasts. Cytosolic XRCC5 interacted with the Cu chaperone and detoxification protein human Atox1 homologue (HAH), and down regulation of XRCC5 expression using siRNA led to enhanced HAH expression when cells were exposed to Cu. XRCC5 could also be purified from cytosolic extracts using a Cu-loaded column. These findings provide further evidence that cytosolic XRCC5 has a key role in protection against DNA oxidation from Cu, through either direct sequestration or signaling through other Cu-detoxification molecules. Our findings have important implications for the development of therapeutic treatments targeting Cu in neurodegeneration and/or cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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34. Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in a HCV/HIV co-infected group with reduced liver disease.
- Author
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Berzsenyi MD, Woollard DJ, McLean CA, Preiss S, Perreau VM, Beard MR, Scott Bowden D, Cowie BC, Li S, Mijch AM, and Roberts SK
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adult, CD3 Complex genetics, CD3 Complex metabolism, Coinfection, Cytokines blood, Down-Regulation immunology, Female, Flaviviridae Infections blood, Flaviviridae Infections complications, GB virus C immunology, HIV Infections immunology, Hepatitis C complications, Hepatitis C immunology, Hepatitis C metabolism, Hepatitis C pathology, Hepatitis, Viral, Human blood, Hepatitis, Viral, Human complications, Hepatitis, Viral, Human genetics, Humans, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) genetics, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Male, Microarray Analysis, Middle Aged, Phosphoproteins genetics, Phosphoproteins metabolism, RNA, Viral blood, Severity of Illness Index, Signal Transduction genetics, Signal Transduction immunology, Th1 Cells metabolism, Th2 Cells metabolism, Down-Regulation genetics, Flaviviridae Infections genetics, Flaviviridae Infections metabolism, GB virus C metabolism, HIV Infections complications, Hepatitis, Viral, Human metabolism
- Abstract
Background & Aims: Studies have shown that GB virus C (GBV-C) infection leads to reduced liver disease in hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection. Considering that the underlying mechanism(s) are unknown, we aim to identify differential gene and protein expression associated with GBV-C in HCV/HIV co-infection that may be responsible for reduced liver disease., Methods: Liver, peripheral blood mononuclear cells (PBMCs), and plasma samples were collected from 43 HCV/HIV patients. Plasma was tested for GBV-C RNA by RT-PCR with NS5B gene primers. A microarray was performed on the liver and RT-qPCRs on the liver/PBMC samples. Hepatic protein expression was measured by immunohistochemistry., Results: Sixteen out of 43 patients had GBV-C RNA. GBV-C was associated with reduced hepatic fibrosis (p=0.005) and inflammation (p=0.007). The microarray analysis of the liver samples (n=10) showed down-regulation of genes critical to intra-hepatic T-cell signaling associated with GBV-C. Quantitative RT-PCR of the liver samples (n=13) confirmed the down-regulation of lymphocyte-specific protein tyrosine kinase (LCK) (p=0.02) and docking protein 2 (DOK2) (p=0.04). No differences in the expression levels of these genes were observed in PBMCs (n=22) according to the GBV-C status. The hepatic expression of the LCK protein, measured by immunohistochemistry (n=36), was decreased in CD3-positive T-cells within portal tracts associated with GBV-C (p=0.003). This remained significant in multivariate analysis controlling for hepatic fibrosis and inflammation (p=0.027). No differences were observed in plasma cytokine concentrations (n=25) or ex-vivo peripheral T-cell responses (n=13) versus GBV-C status., Conclusions: GBV-C infection is associated with down-regulation of critical genes involved in intra-hepatic T-cell signaling in HCV/HIV co-infection. This may be relevant to the pathogenesis of reduced HCV-related liver disease in HIV co-infection., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2011
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35. Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination.
- Author
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Cate HS, Sabo JK, Merlo D, Kemper D, Aumann TD, Robinson J, Merson TD, Emery B, Perreau VM, and Kilpatrick TJ
- Subjects
- Animals, Antimetabolites, Bone Morphogenetic Protein 4 antagonists & inhibitors, Bone Morphogenetic Protein 4 genetics, Bone Morphogenetic Protein 4 physiology, Bone Morphogenetic Protein Receptors antagonists & inhibitors, Bone Morphogenetic Proteins genetics, Brain cytology, Brain immunology, Bromodeoxyuridine, Carrier Proteins pharmacology, Cell Count, Cell Differentiation drug effects, Cell Lineage, Cell Proliferation drug effects, Cerebral Ventricles drug effects, Cuprizone, Demyelinating Diseases chemically induced, Injections, Intraventricular, Mice, Mice, Inbred C57BL, Microdissection, Monoamine Oxidase Inhibitors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Astrocytes drug effects, Bone Morphogenetic Proteins physiology, Cerebral Ventricles pathology, Demyelinating Diseases pathology, Oligodendroglia drug effects, Signal Transduction physiology
- Abstract
The adult subventricular zone (SVZ) is a potential source of precursor cells to replace neural cells lost during demyelination. To better understand the molecular events that regulate neural precursor cell responsiveness in this context we undertook a microarray and quantitative PCR based analysis of genes expressed within the SVZ during cuprizone-induced demyelination. We identified an up-regulation of the genes encoding bone morphogenic protein 4 (BMP4) and its receptors. Immunohistochemistry confirmed an increase in BMP4 protein levels and also showed an increase in phosphorylated SMAD 1/5/8, a key component of BMP4 signalling, during demyelination. In vitro analysis revealed that neural precursor cells isolated from demyelinated animals, as well as those treated with BMP4, produce more astrocytes. Similarly, there were increased numbers of astrocytes in vivo within the SVZ during demyelination. Intraventricular infusion of Noggin, an endogenous antagonist of BMP4, during cuprizone-induced demyelination reduced pSMAD1/5/8, decreased astrocyte numbers and increased oligodendrocyte numbers in the SVZ. Our results suggest that lineage commitment of SVZ neural precursor cells is altered during demyelination and that BMP signalling plays a role in this process., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)
- Published
- 2010
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36. A domain level interaction network of amyloid precursor protein and Abeta of Alzheimer's disease.
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Perreau VM, Orchard S, Adlard PA, Bellingham SA, Cappai R, Ciccotosto GD, Cowie TF, Crouch PJ, Duce JA, Evin G, Faux NG, Hill AF, Hung YH, James SA, Li QX, Mok SS, Tew DJ, White AR, Bush AI, Hermjakob H, and Masters CL
- Subjects
- Humans, Protein Binding, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Systems Biology
- Abstract
The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal "toxic moiety" of Alzheimer's disease. However, despite much work focused on both Abeta and its parent protein, amyloid precursor protein (APP), the functional roles of APP and its cleavage products remain to be fully elucidated. Protein-protein interaction networks can provide insight into protein function, however, high-throughput data often report false positives and are in frequent disagreement with low-throughput experiments. Moreover, the complexity of the CNS is likely to be under represented in such databases. Therefore, we curated the published work characterizing both APP and Abeta to create a protein interaction network of APP and its proteolytic cleavage products, with annotation, where possible, to the level of APP binding domain and isoform. This is the first time that an interactome has been refined to domain level, essential for the interpretation of APP due to the presence of multiple isoforms and processed fragments. Gene ontology and network analysis were used to identify potentially novel functional relationships among interacting proteins.
- Published
- 2010
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37. Axonal mRNA in uninjured and regenerating cortical mammalian axons.
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Taylor AM, Berchtold NC, Perreau VM, Tu CH, Li Jeon N, and Cotman CW
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- Animals, Axons chemistry, Axotomy, Cells, Cultured, Cerebral Cortex chemistry, In Vitro Techniques, Neurogenesis physiology, Oligonucleotide Array Sequence Analysis methods, RNA, Messenger biosynthesis, RNA, Messenger genetics, Rats, Rats, Sprague-Dawley, Axons physiology, Cerebral Cortex physiology, Nerve Regeneration physiology, RNA, Messenger isolation & purification
- Abstract
Using a novel microfluidic chamber that allows the isolation of axons without contamination by nonaxonal material, we have for the first time purified mRNA from naive, matured CNS axons, and identified the presence of >300 mRNA transcripts. We demonstrate that the transcripts are axonal in nature, and that many of the transcripts present in uninjured CNS axons overlap with those previously identified in PNS injury-conditioned DRG axons. The axonal transcripts detected in matured cortical axons are enriched for protein translational machinery, transport, cytoskeletal components, and mitochondrial maintenance. We next investigated how the axonal mRNA pool changes after axotomy, revealing that numerous gene transcripts related to intracellular transport, mitochondria and the cytoskeleton show decreased localization 2 d after injury. In contrast, gene transcripts related to axonal targeting and synaptic function show increased localization in regenerating cortical axons, suggesting that there is an increased capacity for axonal outgrowth and targeting, and increased support for synapse formation and presynaptic function in regenerating CNS axons after injury. Our data demonstrate that CNS axons contain many mRNA species of diverse functions, and suggest that, like invertebrate and PNS axons, CNS axons synthesize proteins locally, maintaining a degree of autonomy from the cell body.
- Published
- 2009
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38. Current and future applications of transcriptomics for discovery in CNS disease and injury.
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Munro KM and Perreau VM
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- Animals, Biomedical Research methods, Biomedical Research trends, Humans, Multiple Sclerosis genetics, Multiple Sclerosis metabolism, Nerve Regeneration physiology, Neurons metabolism, Stem Cells metabolism, Central Nervous System injuries, Central Nervous System metabolism, Central Nervous System Diseases genetics, Central Nervous System Diseases metabolism, Gene Expression Profiling methods, Gene Expression Profiling trends
- Abstract
The central nervous system (CNS) displays heterogeneity at regional, cellular and subcellular levels, making analysis of transcriptomic events accompanying neural injury particularly challenging. Microarray technology provides methods for elucidating global changes in neural gene expression and discovery of signalling pathways within this complex biological network. The lack of suitable and sufficient human CNS tissue along with its inherent variability means that diverse animal models of both multiple sclerosis and neurotrauma are vital for examining the pathophysiological changes accompanying neural injury resulting from disease or trauma. Gene expression profiling of these models is providing valuable information about mechanisms of damage, repair and regeneration and candidate treatments. In vitro models of neural injury are also proving useful, and transcriptomics is enhancing our understanding of the properties of neural stem cells with a view to their therapeutic application in neural repair. Thoughtful experimental design and analysis of microarray experiments is crucial for extracting biological meaning from the vast amount of data produced. In this review we discuss the current and emerging application of transcriptomics for the study of neural function in health, disease and injury., (Copyright (c) 2009 S. Karger AG, Basel.)
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- 2009
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39. Investigating copper-regulated protein expression in Menkes fibroblasts using antibody microarrays.
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Du T, La Fontaine SL, Abdo M, Bellingham SA, Greenough M, Volitakis I, Cherny RA, Bush AI, Hudson PJ, Camakaris J, Mercer JF, Crouch PJ, Masters CL, Perreau VM, and White AR
- Subjects
- Adenosine Triphosphatases chemistry, Adenosine Triphosphatases metabolism, Antigens, Nuclear biosynthesis, Biological Transport, Cation Transport Proteins chemistry, Cation Transport Proteins metabolism, Computational Biology methods, Copper-Transporting ATPases, DNA chemistry, DNA-Binding Proteins biosynthesis, Humans, Ku Autoantigen, Neurodegenerative Diseases metabolism, Oligonucleotide Array Sequence Analysis, Oxygen chemistry, Protein Array Analysis, Proteomics methods, Software, Adenosine Triphosphatases genetics, Cation Transport Proteins genetics, Copper chemistry, Fibroblasts metabolism
- Abstract
Neurodegenerative illnesses are characterized by aberrant metabolism of biometals such as copper (Cu), zinc (Zn) and iron (Fe). However, little is known about the metabolic effects associated with altered metal homeostasis. In this study, we used an in vitro model of altered Cu homeostasis to investigate how Cu regulates cellular protein expression. Human fibroblasts containing a natural deletion mutation of the Menkes (MNK) ATP7A Cu transporter (MNK deleted) were compared to fibroblasts overexpressing ATP7A (MNK transfected). Cultures of MNK-transfected (Low-Cu) cells exhibited 95% less intracellular Cu than MNK-deleted (High-Cu) cells. Comparative proteomic analysis of the two cell-lines was performed using antibody microarrays, and significant differential protein expression was observed between Low-Cu and High-Cu cell-lines. Western blot analysis confirmed the altered protein expression of Ku80, nexilin, L-caldesmon, MAP4, Inhibitor 2 and DNA topoisomerase I. The top 50 altered proteins were analysed using the software program Pathway Studio (Ariadne Genomics) and revealed a significant over-representation of proteins involved in DNA repair and maintenance. Further analysis confirmed that expression of the DNA repair protein Ku80 was dependent on cellular Cu homeostasis and that Low-Cu levels in fibroblasts resulted in elevated susceptibility to DNA oxidation.
- Published
- 2008
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40. The minimum information required for reporting a molecular interaction experiment (MIMIx).
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Orchard S, Salwinski L, Kerrien S, Montecchi-Palazzi L, Oesterheld M, Stümpflen V, Ceol A, Chatr-aryamontri A, Armstrong J, Woollard P, Salama JJ, Moore S, Wojcik J, Bader GD, Vidal M, Cusick ME, Gerstein M, Gavin AC, Superti-Furga G, Greenblatt J, Bader J, Uetz P, Tyers M, Legrain P, Fields S, Mulder N, Gilson M, Niepmann M, Burgoon L, De Las Rivas J, Prieto C, Perreau VM, Hogue C, Mewes HW, Apweiler R, Xenarios I, Eisenberg D, Cesareni G, and Hermjakob H
- Subjects
- Humans, Internationality, Databases, Protein standards, Guidelines as Topic, Information Storage and Retrieval standards, Protein Interaction Mapping standards, Proteomics standards, Research standards
- Abstract
A wealth of molecular interaction data is available in the literature, ranging from large-scale datasets to a single interaction confirmed by several different techniques. These data are all too often reported either as free text or in tables of variable format, and are often missing key pieces of information essential for a full understanding of the experiment. Here we propose MIMIx, the minimum information required for reporting a molecular interaction experiment. Adherence to these reporting guidelines will result in publications of increased clarity and usefulness to the scientific community and will support the rapid, systematic capture of molecular interaction data in public databases, thereby improving access to valuable interaction data.
- Published
- 2007
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41. Effects of melatonin and age on gene expression in mouse CNS using microarray analysis.
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Sharman EH, Bondy SC, Sharman KG, Lahiri D, Cotman CW, and Perreau VM
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- Acute-Phase Proteins biosynthesis, Animals, Arylalkylamine N-Acetyltransferase biosynthesis, Central Nervous System drug effects, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Lipocalin-2, Lipocalins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Oncogene Proteins biosynthesis, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptor, Melatonin, MT1 biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Aging physiology, Central Nervous System metabolism, Gene Expression drug effects, Melatonin pharmacology
- Abstract
The expression levels of a number of genes associated with inflammation and immune function change with advancing age. Melatonin modulates gene expression levels of several of these genes. Therefore the declining levels of melatonin associated with age may play a role in the physiological effects of aging. We used oligonucleotide microarrays to measure age-related changes in mRNA expression in the murine CNS, and to study the effect of prolonged administration of dietary melatonin upon these changes. CB6F1 male mice were fed 40 ppm melatonin for 2.1 months prior to sacrifice at age 26.5 months, and compared with both age-matched controls and young, 4.5-month-old untreated controls. Total RNA was extracted from whole brain (excluding cerebellum and brain stem) and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. The expression of a substantial number of genes was modulated by melatonin treatment and changes in selected genes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A subset of these genes did not change with age. Conversely, some genes modulated by age were also modulated by melatonin treatment. In general, melatonin treatment drove the expression levels of these genes closer to the expression levels detected in the younger animals. Notably, the abundance of lipocalin 2 (Lcn2) mRNA increased with age and was decreased in old animals treated with melatonin. Lcn2 is a member of the acute phase response family of proteins and its mRNA levels in the brain increase in response to inflammation. Many of the genes with expression reduced by melatonin are involved in inflammation and the immune system. This suggests that melatonin treatment may influence the inflammatory responses of old animals, driving them to resemble more closely those occurring in young animals.
- Published
- 2007
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42. Melatonin treatment in old mice enables a more youthful response to LPS in the brain.
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Perreau VM, Bondy SC, Cotman CW, Sharman KG, and Sharman EH
- Subjects
- Aging metabolism, Animals, Dietary Supplements, Drug Synergism, Gene Expression drug effects, Injections, Intraperitoneal, Male, Melatonin administration & dosage, Mice, Mice, Inbred Strains, Microarray Analysis, Oligonucleotide Array Sequence Analysis, RNA, Messenger metabolism, Aging physiology, Brain drug effects, Lipopolysaccharides pharmacology, Melatonin pharmacology
- Abstract
Melatonin modulates the expression of a number of genes related to inflammation and immunity. Declining levels of melatonin with age may thus relate to some of the changes in immune function that occur with age. mRNA expression levels in murine CNS were measured using oligonucleotide microarrays in order to determine whether a dietary melatonin supplement may modify age-related changes in the response to an inflammatory challenge. CB6F1 male mice were fed 40-ppm melatonin for 9 weeks prior to sacrifice at 26.5 months of age, and compared with age-matched untreated controls and 4.5-month-old controls. A subset of both young and old animals was injected i.p. with lipopolysaccharide (LPS). After 3 h, total RNA was extracted from whole brain (excluding brain stem and cerebellum), and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. Data were analyzed in Dchip and GeneSpring. Melatonin treatment markedly altered the response in gene expression of older animals subjected to an LPS challenge. These changes in general, caused the response to more closely resemble that of young animals subjected to the same LPS challenge. Thus melatonin treatment effects a major shift in the response of the CNS to an inflammatory challenge, causing a transition to a more youthful mRNA expression profile.
- Published
- 2007
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43. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease.
- Author
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Adlard PA, Perreau VM, Pop V, and Cotman CW
- Subjects
- Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor genetics, Analysis of Variance, Animals, Aspartic Acid Endopeptidases, Blotting, Western methods, Brain metabolism, Disease Models, Animal, Endopeptidases metabolism, Enzyme-Linked Immunosorbent Assay methods, Female, Immunohistochemistry methods, Male, Mice, Mice, Transgenic, RNA, Messenger biosynthesis, Reverse Transcriptase Polymerase Chain Reaction methods, Time Factors, Alzheimer Disease metabolism, Alzheimer Disease rehabilitation, Amyloid metabolism, Physical Conditioning, Animal physiology
- Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.
- Published
- 2005
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44. The exercise-induced expression of BDNF within the hippocampus varies across life-span.
- Author
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Adlard PA, Perreau VM, and Cotman CW
- Subjects
- Age Factors, Animals, Brain-Derived Neurotrophic Factor genetics, Enzyme-Linked Immunosorbent Assay methods, Exons, Mice, Mice, Inbred C57BL, RNA, Messenger biosynthesis, Reverse Transcriptase Polymerase Chain Reaction methods, Time Factors, Aging physiology, Brain-Derived Neurotrophic Factor metabolism, Gene Expression Regulation physiology, Hippocampus metabolism, Physical Conditioning, Animal physiology
- Abstract
Voluntary exercise increases hippocampal brain-derived neurotrophic factor (BDNF) expression in young animals. In this investigation we examined the induction of BDNF protein in the hippocampus of young (2 months), late middle-aged (15 months) and old (24 months) animals over 4 weeks of exercise. Average running distances decreased with age, with the old animals also maintaining a constant level of activity over time, whereas the other groups tended to increase their average running distance. All animals demonstrated a biphasic profile of BDNF protein induction, with a significant (P<0.05) increase after 1 week of exercise followed by a decrease to near sedentary levels at 2 weeks. After this, BDNF protein levels increased significantly (P<0.05), as compared to baseline, primarily only in the young animals. In whole hippocampal homogenates, only particular BDNF mRNA exons were significantly (P<0.05) changed as a result of exercise, with the largest induction occurring in young animals. BDNF protein induction may, therefore, not be directly correlated with significant mRNA changes. Exercise may represent a therapeutic tool for disorders which involve a decrease in BDNF.
- Published
- 2005
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45. Exercise-induced gene expression changes in the rat spinal cord.
- Author
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Perreau VM, Adlard PA, Anderson AJ, and Cotman CW
- Subjects
- Animals, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Enzyme-Linked Immunosorbent Assay, Gene Expression Profiling, Male, Oligonucleotide Array Sequence Analysis, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Spinal Cord physiopathology, Biomarkers metabolism, Gene Expression, Physical Conditioning, Animal, Spinal Cord metabolism
- Abstract
There is growing evidence that exercise benefits recovery of neuromuscular function from spinal cord injury (SCI). However, the effect of exercise on gene expression in the spinal cord is poorly understood. We used oligonucleotide microarrays to compare thoracic and lumbar regions of spinal cord of either exercising (voluntary wheel running for 21 days) or sedentary rats. The expression data were filtered using statistical tests for significance, and K-means clustering was then used to segregate lists of significantly changed genes into sets based upon expression patterns across all experimental groups. Levels of brain-derived neurotrophic factor (BDNF) protein were also measured after voluntary exercise, across different regions of the spinal cord. BDNF mRNA increased with voluntary exercise, as has been previously shown for other forms of exercise, contributed to by increases in both exon I and exon III. The exercise-induced gene expression changes identified by microarray analysis are consistent with increases in pathways promoting neuronal health, signaling, remodeling, cellular transport, and development of oligodendrocytes. Taken together these data suggest cellular pathways through which exercise may promote recovery in the SCI population.
- Published
- 2005
- Full Text
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46. Retardation of brain aging by chronic treatment with melatonin.
- Author
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Bondy SC, Lahiri DK, Perreau VM, Sharman KZ, Campbell A, Zhou J, and Sharman EH
- Subjects
- Aging physiology, Animals, Brain physiopathology, Cytokines metabolism, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Humans, Inflammation drug therapy, Inflammation etiology, Neurodegenerative Diseases complications, Oxidative Stress drug effects, Aging drug effects, Brain drug effects, Melatonin administration & dosage, Neurodegenerative Diseases drug therapy
- Abstract
Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age-related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.
- Published
- 2004
- Full Text
- View/download PDF
47. Spatial and temporal gene expression profiling of the contused rat spinal cord.
- Author
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Aimone JB, Leasure JL, Perreau VM, and Thallmair M
- Subjects
- Animals, Apoptosis genetics, Cathepsins metabolism, Cholesterol metabolism, DNA Fingerprinting, Female, Gene Expression Profiling, Genes, cdc physiology, Inflammation genetics, Inflammation metabolism, Inflammation physiopathology, Neovascularization, Physiologic genetics, Oxidative Stress genetics, Phagocytosis genetics, Rats, Rats, Inbred F344, Reaction Time genetics, Spinal Cord physiopathology, Spinal Cord Injuries metabolism, Spinal Cord Injuries physiopathology, Synaptic Transmission genetics, Time Factors, Gene Expression Regulation, Spinal Cord metabolism, Spinal Cord Injuries genetics
- Abstract
Microarray technology was used to examine gene expression changes following contusive injury of the adult rat spinal cord. To obtain a global understanding of the changes triggered by the injury, differential gene expression was examined spatially, using tissue samples from the epicenter of injury as well as 1 cm rostral and 1 cm caudal to the epicenter, and temporally, at 3 h, 24 h, 7 days, and 35 days post-injury. To filter out gene expression changes that were due to the laminectomy, samples of contused tissue were compared to laminectomy-only controls. We took advantage of four different, complementary methods of data analysis to detect differentially expressed genes. We have identified functional groups of genes that are differentially regulated in our model, including those associated with apoptosis, cell cycle, inflammation, and cholesterol metabolism. Our analysis has led to the identification of novel potential therapeutic targets within each group of genes that is discussed.
- Published
- 2004
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48. Neutralization of the chemokine CXCL10 enhances tissue sparing and angiogenesis following spinal cord injury.
- Author
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Glaser J, Gonzalez R, Perreau VM, Cotman CW, and Keirstead HS
- Subjects
- Animals, Antibodies administration & dosage, Blood Vessels metabolism, Brain Stem metabolism, Chemokine CXCL10, Chemokines, CXC immunology, Electrophoretic Mobility Shift Assay methods, Female, Immunohistochemistry methods, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis methods, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Spinal Cord metabolism, Spinal Cord Injuries metabolism, Time Factors, Up-Regulation genetics, Chemokines, CXC metabolism, Neovascularization, Physiologic physiology, Spinal Cord Injuries physiopathology, Wound Healing physiology
- Abstract
After spinal cord injury, there is a chemoattractant-mediated inflammatory response that is associated with secondary degeneration. The chemoattractant CXCL10 recruits CD4 Th1 cells via the CXCR3A receptor and inhibits growth and chemotaxis of endothelial cells via the CXCR3B receptor. To test the hypothesis that CXCL10 inhibits angiogenesis following spinal cord injury, we assayed the brainstems and spinal cords of spinal cord-injured mice treated with anti-CXCL10 antibodies for expression of angiogenesis-associated genes and quantified blood vessels within their spinal cords. Brainstem microarray analysis indicated eight angiogenesis-associated genes that had significantly higher expression levels in the treated mice than in the untreated mice. Ribonuclease protection assays of the spinal cords showed a significant increase in eight angiogenesis-associated genes in treated animals compared with untreated animals. Histological analysis of the spinal cords of treated and untreated mice showed a significant increase in the number of blood vessels in treated animals. We conclude that CXCL10 plays a critical role in vasculature remodeling following spinal cord injury and that angiogenesis is enhanced following anti-CXCL10 treatment of spinal cord injuries. Improved blood flow and oxygen supply to the injury site may contribute to the functional improvement associated with this treatment.
- Published
- 2004
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49. The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise.
- Author
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Adlard PA, Perreau VM, Engesser-Cesar C, and Cotman CW
- Subjects
- Analysis of Variance, Animals, Behavior, Animal, Brain-Derived Neurotrophic Factor genetics, Enzyme-Linked Immunosorbent Assay methods, Escape Reaction physiology, Exons, Male, Maze Learning physiology, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction methods, Time Factors, Brain-Derived Neurotrophic Factor metabolism, Hippocampus metabolism, Physical Conditioning, Animal physiology
- Abstract
In this study we examined the timecourse of induction of brain-derived neurotrophic factor (BDNF) mRNA and protein after 1, 3, 5, 7, 14 and 28 days of exercise in the rat. To measure the expression of mRNA for individual BDNF exons we utilized a semi-quantitative RT-PCR technique, while BDNF protein was assessed using commercial ELISA kits. We demonstrated that the distance run by animals increased significantly (P<0.05) after 4 weeks. BDNF protein was significantly (P<0.05) increased after 4 weeks of exercise, while the mRNA for individual BDNF exons increased significantly (P<0.05) over the timecourse (exon I after 1 and 28 days and exons II and V after 28 days). The Morris water maze was then utilized to demonstrate that 3 weeks of prior exercise enhanced the rate of learning on this task. Exercise, therefore, was shown to modulate BDNF induction in a time-dependent manner, and this may translate to improvements in neurotrophin-mediated tasks within the CNS.
- Published
- 2004
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50. Effects of exercise on gene-expression profile in the rat hippocampus.
- Author
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Tong L, Shen H, Perreau VM, Balazs R, and Cotman CW
- Subjects
- Aging genetics, Aging metabolism, Animals, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Energy Metabolism genetics, Environment, Controlled, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Hippocampus cytology, Immune System metabolism, Male, Nerve Tissue Proteins biosynthesis, Neuropeptides genetics, Neuropeptides metabolism, Oligonucleotide Array Sequence Analysis, Protein Transport genetics, Rats, Rats, Sprague-Dawley, Gene Expression Regulation physiology, Hippocampus metabolism, Nerve Tissue Proteins genetics, Neuronal Plasticity genetics, Physical Conditioning, Animal physiology, Physical Exertion physiology, Transcription, Genetic genetics, Up-Regulation genetics
- Abstract
Exercise has beneficial effects on brain function, including the promotion of plasticity and the enhancement of learning and memory performance. Previously we found that exercise increases the expression of certain neurotrophic factors including brain derived neurotrophic factor in the rat hippocampus. To further explore the molecular mechanisms underlying these changes, we used high-density oligonucleotide microarrays containing probe sets representing approximately 5000 genes to analyze the level of gene transcripts in the hippocampus of rats voluntary running for 3 weeks in comparison with sedentary animals. An improved statistical approach for the analysis of DNA microarray data, Cyber-T, was utilized in data analysis. Here we show that exercise leads to changes in the level of a large number of gene transcripts, many of which are known to be associated with neuronal activity, synaptic structure, and neuronal plasticity. Our data indicate that exercise elicits a differential gene expression pattern with significant changes in genes of relevance for brain function.
- Published
- 2001
- Full Text
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