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Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology.

Parente MK, Rozen R, Cearley CN, Wolfe JH - PLoS ONE (2012)

Bottom Line: We found that patterns of aberrant gene expression and involvement of multiple molecular and cellular systems varied significantly between brain regions.A number of changes revealed unexpected system and process alterations, such as up-regulation of the immune system with few inflammatory changes (a significant difference from the closely related MPS IIIb model), down-regulation of major oligodendrocyte genes even though white matter changes are not a feature histopathologically, and a plethora of developmental gene changes.In addition, the variation in gene dysregulation between brain regions indicates that different neuropathologic mechanisms may predominate within different regions of a diseased brain caused by a single gene mutation.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The characteristic neurological feature of many neurogenetic diseases is intellectual disability. Although specific neuropathological features have been described, the mechanisms by which specific gene defects lead to cognitive impairment remain obscure. To gain insight into abnormal functions occurring secondary to a single gene defect, whole transcriptome analysis was used to identify molecular and cellular pathways that are dysregulated in the brain in a mouse model of a lysosomal storage disorder (LSD) (mucopolysaccharidosis [MPS] VII). We assayed multiple anatomical regions separately, in a large cohort of normal and diseased mice, which greatly increased the number of significant changes that could be detected compared to past studies in LSD models. We found that patterns of aberrant gene expression and involvement of multiple molecular and cellular systems varied significantly between brain regions. A number of changes revealed unexpected system and process alterations, such as up-regulation of the immune system with few inflammatory changes (a significant difference from the closely related MPS IIIb model), down-regulation of major oligodendrocyte genes even though white matter changes are not a feature histopathologically, and a plethora of developmental gene changes. The involvement of multiple neural systems indicates that the mechanisms of neuropathology in this type of disease are much broader than previously appreciated. In addition, the variation in gene dysregulation between brain regions indicates that different neuropathologic mechanisms may predominate within different regions of a diseased brain caused by a single gene mutation.

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Changes in lysosome genes across regions in MPS VII brain.The key across the bottom shows the magnitude of significance coded in shades of gray and the fold change and direction coded in shades of red for increased expression and shades of green for decreased expression (the same key is used in figures 3–8). The values for each gene in each region are in the boxes. Gusb was down-regulated in all regions, as expected, while other normal lysosomal genes were up-regulated consistent with enzymatic activity data.
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pone-0032419-g002: Changes in lysosome genes across regions in MPS VII brain.The key across the bottom shows the magnitude of significance coded in shades of gray and the fold change and direction coded in shades of red for increased expression and shades of green for decreased expression (the same key is used in figures 3–8). The values for each gene in each region are in the boxes. Gusb was down-regulated in all regions, as expected, while other normal lysosomal genes were up-regulated consistent with enzymatic activity data.

Mentions: Expression of the Gusb gene was significantly down-regulated in all brain regions in the MPS VII mice (average p* = 1.4×10−7). This was expected because the mutation is at the 3′ end of the gene and results in a very low level of transcription due to instability of the mutant mRNA [21]. Many other lysosomal genes were up-regulated (Figure 2), which was also expected since secondary elevation of enzymatic activities of other lysosomal enzymes is a common feature in LSDs, including MPS VII [22], [23], [24]. The reduced expression in Gusb and increased expression of Hexb were confirmed by RT-PCR (Fig. S1). In addition to the genes that are listed in the DAVID Lysosome cluster, 5 more recently identified lysosomal genes were also up-regulated [25].


Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology.

Parente MK, Rozen R, Cearley CN, Wolfe JH - PLoS ONE (2012)

Changes in lysosome genes across regions in MPS VII brain.The key across the bottom shows the magnitude of significance coded in shades of gray and the fold change and direction coded in shades of red for increased expression and shades of green for decreased expression (the same key is used in figures 3–8). The values for each gene in each region are in the boxes. Gusb was down-regulated in all regions, as expected, while other normal lysosomal genes were up-regulated consistent with enzymatic activity data.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293807&req=5

pone-0032419-g002: Changes in lysosome genes across regions in MPS VII brain.The key across the bottom shows the magnitude of significance coded in shades of gray and the fold change and direction coded in shades of red for increased expression and shades of green for decreased expression (the same key is used in figures 3–8). The values for each gene in each region are in the boxes. Gusb was down-regulated in all regions, as expected, while other normal lysosomal genes were up-regulated consistent with enzymatic activity data.
Mentions: Expression of the Gusb gene was significantly down-regulated in all brain regions in the MPS VII mice (average p* = 1.4×10−7). This was expected because the mutation is at the 3′ end of the gene and results in a very low level of transcription due to instability of the mutant mRNA [21]. Many other lysosomal genes were up-regulated (Figure 2), which was also expected since secondary elevation of enzymatic activities of other lysosomal enzymes is a common feature in LSDs, including MPS VII [22], [23], [24]. The reduced expression in Gusb and increased expression of Hexb were confirmed by RT-PCR (Fig. S1). In addition to the genes that are listed in the DAVID Lysosome cluster, 5 more recently identified lysosomal genes were also up-regulated [25].

Bottom Line: We found that patterns of aberrant gene expression and involvement of multiple molecular and cellular systems varied significantly between brain regions.A number of changes revealed unexpected system and process alterations, such as up-regulation of the immune system with few inflammatory changes (a significant difference from the closely related MPS IIIb model), down-regulation of major oligodendrocyte genes even though white matter changes are not a feature histopathologically, and a plethora of developmental gene changes.In addition, the variation in gene dysregulation between brain regions indicates that different neuropathologic mechanisms may predominate within different regions of a diseased brain caused by a single gene mutation.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The characteristic neurological feature of many neurogenetic diseases is intellectual disability. Although specific neuropathological features have been described, the mechanisms by which specific gene defects lead to cognitive impairment remain obscure. To gain insight into abnormal functions occurring secondary to a single gene defect, whole transcriptome analysis was used to identify molecular and cellular pathways that are dysregulated in the brain in a mouse model of a lysosomal storage disorder (LSD) (mucopolysaccharidosis [MPS] VII). We assayed multiple anatomical regions separately, in a large cohort of normal and diseased mice, which greatly increased the number of significant changes that could be detected compared to past studies in LSD models. We found that patterns of aberrant gene expression and involvement of multiple molecular and cellular systems varied significantly between brain regions. A number of changes revealed unexpected system and process alterations, such as up-regulation of the immune system with few inflammatory changes (a significant difference from the closely related MPS IIIb model), down-regulation of major oligodendrocyte genes even though white matter changes are not a feature histopathologically, and a plethora of developmental gene changes. The involvement of multiple neural systems indicates that the mechanisms of neuropathology in this type of disease are much broader than previously appreciated. In addition, the variation in gene dysregulation between brain regions indicates that different neuropathologic mechanisms may predominate within different regions of a diseased brain caused by a single gene mutation.

Show MeSH
Related in: MedlinePlus