title: Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling.
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.
authors.affiliation: Department of Biology, St Mary's College of Maryland, St Mary's City, MD 20686, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Myerowitz
authors.forename: Douglas
authors.initials: D
authors.lastname: Lawson
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Yide
authors.initials: Y
authors.lastname: Mi
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D002540:Cerebral Cortex / Q000378:metabolism; D002675:Child, Preschool; D020224:Expressed Sequence Tags; D005678:G(M2) Ganglioside / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D012497:Sandhoff Disease / Q000235:genetics* / Q000378:metabolism; D013661:Tay-Sachs Disease / Q000235:genetics* / Q000378:metabolism
chemical_list: D005678:G(M2) Ganglioside