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: 6.68). 06/2002; 11(11):1343-50.
Source: PubMed

ABSTRACT 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, Jul 17, 2015
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    • "The involvement of the abnormal proliferation of astrocytes in the observed nerve cell death in SD mice is still unclear. However, an increase of chemokine production by astrocytes has been observed in SD mice (Myerowitz et al. 2002). The increased proliferation of astrocytes in SD mice may further increase the amount of cytokines and chemokines thereby damaging nerve cells. "
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    ABSTRACT: Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes the beta-subunit of N-acetyl-beta-hexosaminidase A and B, resulting in the accumulation of the ganglioside GM2. We isolated astrocytes from the neonatal brain of Sandhoff disease model mice in which the N-acetyl-beta-hexosaminidase beta-subunit gene is genetically disrupted (ASD). Glycolipid profiles revealed that GM2/GA2 accumulated in the lysosomes and not on the cell surface of ASD astrocytes. In addition, GM3 was increased on the cell surface. We found remarkable differences in the cell proliferation of ASD astrocytes when compared with cells isolated from wild-type mice, with a faster growth rate of ASD cells. In addition, we observed increased extracellular, signal-regulated kinase (ERK) phosphorylation in ASD cells, but Akt phosphorylation was decreased. Furthermore, the phosphorylation of ERK in ASD cells was not dependent upon extracellular growth factors. Treatment of ASD astrocytes with recombinant N-acetyl-beta-hexosaminidase A resulted in a decrease of their growth rate and ERK phosphorylation. These results indicated that the up-regulation of ERK phosphorylation and the increase in proliferation of ASD astrocytes were dependent upon GM2/GA2 accumulation. These findings may represent a mechanism in linking the nerve cell death and reactive gliosis observed in Sandhoff disease.
    Journal of Neurochemistry 09/2009; 111(4):1031-41. DOI:10.1111/j.1471-4159.2009.06391.x · 4.24 Impact Factor
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    • "The cellular pathology of these diseases is poorly understood and there are currently no licensed treatments available for these neurodegenerative disorders. Multi-factorial downstream pathways appear to be activated in response to lysosomal storage (Jeyakumar et al., 2003; Myerowitz et al., 2002; Phaneuf et al., 1996; Wada et al., 2000); these include inflammatory responses, oxidative stress and neuronal apoptosis. "
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    ABSTRACT: Neurodegeneration is a prominent feature of the gangliosidoses, a group of lysosomal storage diseases. Here we show altered iron homeostasis in mouse models of both GM1 and GM2 gangliosidoses, which are characterized by progressive depletion of iron in brain tissue. This finding contrasts with the findings in many other neurological disorders, where excess iron deposition has been reported. We found that key regulators of iron homeostasis, hepcidin and IL-6, were increased in gangliosidoses mice. In the brain, the principal iron transport and delivery protein transferrin was reduced, accompanied by a progressive inability of the brain to acquire iron from the circulation. Expression of the transferrin receptor was up-regulated reciprocally. Despite the deregulation of iron homeostasis administration of iron prolonged survival in the diseased mice by up to 38%, with onset of disease delayed and motor function preserved.
    Neurobiology of Disease 07/2009; 34(3):406-16. DOI:10.1016/j.nbd.2009.01.015 · 5.20 Impact Factor
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    • "Sandhoff disease model mice established by means of Hexb disruption exhibit neurosomatic manifestations quite similar to those in SD patients (Sango et al. 1995). Previous studies revealed the progressive increase in microglial activation/expansion and the following neuronal apoptosis in the brain and spinal cord of SD mice, suggesting that microglial activation should be involved in the neurodegenerative mechanism in SD (Huang et al. 1997; Wada et al. 2000; Myerowitz et al. 2002; Jeyakumar et al. 2003), which is also observed in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and ischemia (González-Scarano and Baltuch 1999; Eikelenboom et al. 2002; Wu et al. 2002). "
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    ABSTRACT: Sandhoff disease (SD) is a lysosomal beta-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including terminal N-acetylglucosamine-oligosaccharides and GM2 ganglioside, and progressive neurodegeneration. Our previous study demonstrated remarkable induction of macrophage inflammatory factor-1alpha (MIP-1alpha) in microglia in the brains of SD model mice as a putative pathogenic factor for SD via microglia-mediated neuroinflammation. In this study, we established microglial cell lines (WT- and SD-Mg) from wild-type and SD mice, and first demonstrated the enhanced production of MIP-1alpha in SD-Mg. Inhibitors of protein kinase C (PKC) and Akt reduced the production of MIP-1alpha by SD-Mg. Elevated activation of Akt and partial translocation of PKC isozymes (alpha, betaI, betaII, and delta) from the cytoplasm to the membrane in SD-Mg were also revealed by means of immunoblotting. Furthermore, it was demonstrated that intracellular extracellular signal-regulated kinase, c-Jun N-terminal kinase, and phospholipase C (PLC), but not phosphoinositide 3-kinase, should contribute to the induction of MIP-1alpha in SD-Mg, and that PLC could independently regulate the activation of both PKC and Akt. We proposed here that the deregulated activation of PLC should cause the enhanced MIP-1alpha production via plural signaling pathways mediated by PKC and Akt, followed by extracellular signal-regulated kinase and c-Jun N-terminal kinase, in SD-Mg.
    Journal of Neurochemistry 04/2009; 109(5):1215-24. DOI:10.1111/j.1471-4159.2009.06041.x · 4.24 Impact Factor
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