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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    • "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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    • "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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    • "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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