Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling

Department of Biology, St Mary's College of Maryland, St Mary's City, MD 20686, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2002; 11(11):1343-50.
Source: PubMed


Tay-Sachs and Sandhoff diseases are lysosomal storage disorders characterized by the absence of beta-hexosaminidase activity and the accumulation of GM2 ganglioside in neurons. In each disorder, a virtually identical course of neurodegeneration begins in infancy and leads to demise generally by 4-6 years of age. Through serial analysis of gene expression (SAGE), we determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatability antigens, the pro-inflammatory cytokine osteopontin, complement components, proteinases and inhibitors, galectins, osteonectin/SPARC, and prostaglandin D2 synthase. The results are consistent with a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

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Available from: Hiroki Mizukami
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    • "Consistently, over expression of Cathepsin D (CTSD) has been reported in the brain of murine models of several other lysosomal diseases such as Gaucher’s disease, Sandhoff disease, GM1 gangliosidoses, Neimann-Pick A [52]. Elevated Ctsb transcripts have also been observed in the brain of Sandhoff and Tay-Sachs patients [53]. In addition to innate immune markers, we also see elevation of transcripts of alpha-N-acetylglucosaminidase (Naglu) and HexosaminidaseB (Hexb), genes linked to lysosomal diseases MPS IIIB and Sandhoff disease respectively. "
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    ABSTRACT: Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.
    Full-text · Article · Oct 2012 · PLoS ONE
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    • "Progressive neuronal GM2 storage is a cardinal characteristic of the HexB−/− mice, followed by neurodegeneration associated with neuronal apoptosis occurring in the central nervous system [3]. Additional studies have demonstrated the presence of reactive microglia and astrocytes in the HexB−/− brain, along with increased levels of inflammation-related genes [4-7]. Deletion of macrophage-inflammatory protein (MIP)1α retarded neurodegeneration in the HexB−/− mouse model [8]. "
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    ABSTRACT: This study evaluated whether GM2 ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB-/- mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB-/- mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB-/- mice from GM2 neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM2 presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored.
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    • "The upregulation of Cst7 in the present BSE model, described in other TSE [18,19,61], can be a consequence of the induction of lysosomal proteases [18] or could have a compensatory role against the accumulation of abnormal protein in some neurodegenerative diseases [8,18,79,80]. The downregulation of the Rtn3 gene observed at 270 dpi may lead to a decrease in the Bcl-2 antiapoptotic function, leading to neuronal death. "
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    ABSTRACT: ABSTRACT: Gene expression analysis has proven to be a very useful tool to gain knowledge of the factors involved in the pathogenesis of diseases, particularly in the initial or preclinical stages. With the aim of finding new data on the events occurring in the Central Nervous System in animals affected with Bovine Spongiform Encephalopathy, a comprehensive genome wide gene expression study was conducted at different time points of the disease on mice genetically modified to model the bovine species brain in terms of cellular prion protein. An accurate analysis of the information generated by microarray technique was the key point to assess the biological relevance of the data obtained in terms of Transmissible Spongiform Encephalopathy pathogenesis. Validation of the microarray technique was achieved by RT-PCR confirming the RNA change and immunohistochemistry techniques that verified that expression changes were translated into variable levels of protein for selected genes. Our study reveals changes in the expression of genes, some of them not previously associated with prion diseases, at early stages of the disease previous to the detection of the pathological prion protein, that might have a role in neuronal degeneration and several transcriptional changes showing an important imbalance in the Central Nervous System homeostasis in advanced stages of the disease. Genes whose expression is altered at early stages of the disease should be considered as possible therapeutic targets and potential disease markers in preclinical diagnostic tool development. Genes non-previously related to prion diseases should be taken into consideration for further investigations.
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