Human Molecular Genetics, 2002, Vol. 11, No. 11 1343-1351
© 2002 Oxford University Press
Molecular pathophysiology in Tay–Sachs and Sandhoff diseases as revealed by gene expression profiling
1Department of Biology, St Mary's College of Maryland, St Mary's City, MD 20686, USA, 2Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA and 3Department of Medical Genetics, Children's National Medical Center, Washington, DC 20010, USA
Received February 7, 2002; Accepted March 19, 2002
Tay–Sachs and Sandhoff diseases are lysosomal storage disorders characterized by the absence of ß-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.
* To whom correspondence should be addressed at: Building 10, Room 9N-314, National Institutes of Health, 10 Center DR MSC 1821, Bethesda, MD 20892-1821, USA. Tel:+1 301 496 4391; Fax:+1 301 496 0839; Email: proia{at}nih.gov
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