Limits...
The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression.

Jokic N, Yip PK, Michael-Titus A, Priestley JV, Malaspina A - BMC Genomics (2010)

Bottom Line: Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS).The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability.In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, UK.

ABSTRACT

Background: Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In this study, we have investigated how a mutation of the superoxide dismutase 1 (SOD1) gene, linked to the development of ALS, modifies the acute response to a gentle mechanical compression of the spinal cord. In a 7-day post-injury time period, we have performed a comparative ontological analysis of the gene expression profiles of injured spinal cords obtained from pre-symptomatic rats over-expressing the G93A-SOD1 gene mutation and from wild type (WT) littermates.

Results: The steady post-injury functional recovery observed in WT rats was accompanied by the early activation at the epicenter of injury of several growth-promoting signals and by the down-regulation of intermediate neurofilaments and of genes involved in the regulation of ion currents at the 7 day post-injury time point. The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability. These molecular changes occurred along with a pronounced atrophy of spinal cord motor neurones in the G93A-SOD1 rats compared to WT littermates after compression injury.

Conclusions: In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.

Show MeSH

Related in: MedlinePlus

Comparative gene expression analysis by High-Throughput GoMiner of spinal cord samples from G93A-SOD1 and WT rats subjected to a mild compression SCI. The heat chart displays the Gene ontology (GO) categories (grouped into main functional headings) computed by High Throughput GoMiner computational analysis of the differentially expressed genes identified in spinal cord from WT and G93A-SOD1 rats after compression SCI, using naive (10 week old) spinal cord tissue from rats of the same genetic type as reference. High Throughput GoMiner defines the biological significance of the gene expression changes according to a multilayered process of statistical processing. GO categories are selected on the basis of their high level of enrichment of the differentially expressed genes, using a false discovery rate correction (FDR) cut off of <0.05. FDR introduces a multiple comparisons correction, allowing the exclusion of those gene categories that would appear enriched simply by chance. Functionally similar GO categories are grouped within the same heading and reported as up-regulated predominantly in G93A-SOD1 spinal cord (A, ↑G93A-SOD1), in WT spinal cord (B. ↑WT), down-regulated in G93A-SOD1 spinal cord (C. ↓G93A-SOD1) and in WT spinal cord (D. ↓WT). The various levels of significance of differential regulation for each gene category are represented in the heat-chart with different colour codes (the correlation between colour codes and FDR values is reported at the bottom of the heat-chart). G93A-SOD1/WT column: Comparison between the gene expression profiles of spinal cord samples from G93A-SOD1 and WT naïve rats (10 week of age).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3020590&req=5

Figure 3: Comparative gene expression analysis by High-Throughput GoMiner of spinal cord samples from G93A-SOD1 and WT rats subjected to a mild compression SCI. The heat chart displays the Gene ontology (GO) categories (grouped into main functional headings) computed by High Throughput GoMiner computational analysis of the differentially expressed genes identified in spinal cord from WT and G93A-SOD1 rats after compression SCI, using naive (10 week old) spinal cord tissue from rats of the same genetic type as reference. High Throughput GoMiner defines the biological significance of the gene expression changes according to a multilayered process of statistical processing. GO categories are selected on the basis of their high level of enrichment of the differentially expressed genes, using a false discovery rate correction (FDR) cut off of <0.05. FDR introduces a multiple comparisons correction, allowing the exclusion of those gene categories that would appear enriched simply by chance. Functionally similar GO categories are grouped within the same heading and reported as up-regulated predominantly in G93A-SOD1 spinal cord (A, ↑G93A-SOD1), in WT spinal cord (B. ↑WT), down-regulated in G93A-SOD1 spinal cord (C. ↓G93A-SOD1) and in WT spinal cord (D. ↓WT). The various levels of significance of differential regulation for each gene category are represented in the heat-chart with different colour codes (the correlation between colour codes and FDR values is reported at the bottom of the heat-chart). G93A-SOD1/WT column: Comparison between the gene expression profiles of spinal cord samples from G93A-SOD1 and WT naïve rats (10 week of age).

Mentions: We have used High Throughput GO-Miner as previously reported [6,21] to obtain an integrated ontological analysis of the gene expression datasets of injured G93A-SOD1 and WT spinal cords. This program identifies gene categories within the Gene Ontology (GO) database that are enriched with the differentially regulated genes under investigation and display a significant false discovery rate (FDR < 0.05), a value which indicates the statistical significance of the identified gene category by eliminating probe signals detected only by chance [21]. Of the 150 gene categories computed by High Throughput GO-Miner, 36 with a broad biological significance and not related to any specific functional or biological mechanism (e.g. GO:0007610_behavior; GO:0019725_cell_homeostasis; GO:0009893_positive_regulation_of_metabolic_process; GO:0042592_homeostatic_process) were excluded from further analysis, as were 66 gene categories showing the same temporal distribution and level of FDR significance in G93A-SOD1 and in WT spinal cord. The time dependent expression of the remaining 48 gene categories has been graphically displayed in a heat-chart, where the FDR value for each gene category at a specific time point is represented with a colour-code (Figure 3). The selected gene categories are grouped into functional headings, according to their "parent-child" relationship and biological affinity. Gene categories found to be up-regulated in G93A-SOD1 spinal cord, those up-regulated in WT spinal cord, those down-regulated in G93A-SOD1 and those down-regulated in WT spinal cord are reported in Figure 3A, B, C and 3D respectively. Those gene categories up-regulated predominantly in G93A-SOD1 spinal cord seem to be mostly detected at 4 hours post-injury (Figure 2A), whereas those differentially regulated in WT spinal cord are identifiable mainly at the 24 hour and 7 day time points (Figure 3B, D). The key changes shown in Figure 3 will now be briefly reviewed:


The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression.

Jokic N, Yip PK, Michael-Titus A, Priestley JV, Malaspina A - BMC Genomics (2010)

Comparative gene expression analysis by High-Throughput GoMiner of spinal cord samples from G93A-SOD1 and WT rats subjected to a mild compression SCI. The heat chart displays the Gene ontology (GO) categories (grouped into main functional headings) computed by High Throughput GoMiner computational analysis of the differentially expressed genes identified in spinal cord from WT and G93A-SOD1 rats after compression SCI, using naive (10 week old) spinal cord tissue from rats of the same genetic type as reference. High Throughput GoMiner defines the biological significance of the gene expression changes according to a multilayered process of statistical processing. GO categories are selected on the basis of their high level of enrichment of the differentially expressed genes, using a false discovery rate correction (FDR) cut off of <0.05. FDR introduces a multiple comparisons correction, allowing the exclusion of those gene categories that would appear enriched simply by chance. Functionally similar GO categories are grouped within the same heading and reported as up-regulated predominantly in G93A-SOD1 spinal cord (A, ↑G93A-SOD1), in WT spinal cord (B. ↑WT), down-regulated in G93A-SOD1 spinal cord (C. ↓G93A-SOD1) and in WT spinal cord (D. ↓WT). The various levels of significance of differential regulation for each gene category are represented in the heat-chart with different colour codes (the correlation between colour codes and FDR values is reported at the bottom of the heat-chart). G93A-SOD1/WT column: Comparison between the gene expression profiles of spinal cord samples from G93A-SOD1 and WT naïve rats (10 week of age).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020590&req=5

Figure 3: Comparative gene expression analysis by High-Throughput GoMiner of spinal cord samples from G93A-SOD1 and WT rats subjected to a mild compression SCI. The heat chart displays the Gene ontology (GO) categories (grouped into main functional headings) computed by High Throughput GoMiner computational analysis of the differentially expressed genes identified in spinal cord from WT and G93A-SOD1 rats after compression SCI, using naive (10 week old) spinal cord tissue from rats of the same genetic type as reference. High Throughput GoMiner defines the biological significance of the gene expression changes according to a multilayered process of statistical processing. GO categories are selected on the basis of their high level of enrichment of the differentially expressed genes, using a false discovery rate correction (FDR) cut off of <0.05. FDR introduces a multiple comparisons correction, allowing the exclusion of those gene categories that would appear enriched simply by chance. Functionally similar GO categories are grouped within the same heading and reported as up-regulated predominantly in G93A-SOD1 spinal cord (A, ↑G93A-SOD1), in WT spinal cord (B. ↑WT), down-regulated in G93A-SOD1 spinal cord (C. ↓G93A-SOD1) and in WT spinal cord (D. ↓WT). The various levels of significance of differential regulation for each gene category are represented in the heat-chart with different colour codes (the correlation between colour codes and FDR values is reported at the bottom of the heat-chart). G93A-SOD1/WT column: Comparison between the gene expression profiles of spinal cord samples from G93A-SOD1 and WT naïve rats (10 week of age).
Mentions: We have used High Throughput GO-Miner as previously reported [6,21] to obtain an integrated ontological analysis of the gene expression datasets of injured G93A-SOD1 and WT spinal cords. This program identifies gene categories within the Gene Ontology (GO) database that are enriched with the differentially regulated genes under investigation and display a significant false discovery rate (FDR < 0.05), a value which indicates the statistical significance of the identified gene category by eliminating probe signals detected only by chance [21]. Of the 150 gene categories computed by High Throughput GO-Miner, 36 with a broad biological significance and not related to any specific functional or biological mechanism (e.g. GO:0007610_behavior; GO:0019725_cell_homeostasis; GO:0009893_positive_regulation_of_metabolic_process; GO:0042592_homeostatic_process) were excluded from further analysis, as were 66 gene categories showing the same temporal distribution and level of FDR significance in G93A-SOD1 and in WT spinal cord. The time dependent expression of the remaining 48 gene categories has been graphically displayed in a heat-chart, where the FDR value for each gene category at a specific time point is represented with a colour-code (Figure 3). The selected gene categories are grouped into functional headings, according to their "parent-child" relationship and biological affinity. Gene categories found to be up-regulated in G93A-SOD1 spinal cord, those up-regulated in WT spinal cord, those down-regulated in G93A-SOD1 and those down-regulated in WT spinal cord are reported in Figure 3A, B, C and 3D respectively. Those gene categories up-regulated predominantly in G93A-SOD1 spinal cord seem to be mostly detected at 4 hours post-injury (Figure 2A), whereas those differentially regulated in WT spinal cord are identifiable mainly at the 24 hour and 7 day time points (Figure 3B, D). The key changes shown in Figure 3 will now be briefly reviewed:

Bottom Line: Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS).The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability.In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, UK.

ABSTRACT

Background: Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In this study, we have investigated how a mutation of the superoxide dismutase 1 (SOD1) gene, linked to the development of ALS, modifies the acute response to a gentle mechanical compression of the spinal cord. In a 7-day post-injury time period, we have performed a comparative ontological analysis of the gene expression profiles of injured spinal cords obtained from pre-symptomatic rats over-expressing the G93A-SOD1 gene mutation and from wild type (WT) littermates.

Results: The steady post-injury functional recovery observed in WT rats was accompanied by the early activation at the epicenter of injury of several growth-promoting signals and by the down-regulation of intermediate neurofilaments and of genes involved in the regulation of ion currents at the 7 day post-injury time point. The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability. These molecular changes occurred along with a pronounced atrophy of spinal cord motor neurones in the G93A-SOD1 rats compared to WT littermates after compression injury.

Conclusions: In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.

Show MeSH
Related in: MedlinePlus