Mucopolysaccharidoses (MPS) are genetically inheritable diseases defined by the inability of the cell to catabolize glycosaminoglycan sugars, causing intra-lysosomal accumulation of the undegraded metabolite. MPS disorders that store the glycosaminoglycan heparan sulfate result in severe neuropathology and are usually lethal within the first few decades of life. The cause of neuropathology in these diseases is unclear but may be associated with the storage of secondary metabolites. Indeed, the secondary accumulation of gangliosides in the brains of MPS disease models deficient in heparan sulfate catabolism has been previously described. Further, preliminary analysis in our lab has revealed a novel mechanism by which heparan sulfate storage in MPSIIIa cells results in the dramatic secondary accumulation of chondoitin/dermatan sulfate. In the first aim of this project we will further characterize the secondary storage of chondroitin/dermatan sulfate by analyzing fibroblasts from additional heparan sulfate storage disorders. Further, we will use the analytical facilities available through Glycotechnology Core at UCSD to screen for the secondary accumulation of additional metabolites such as N- or O-glycans in MPS fibroblasts. To assess whether secondary metabolite storage might contribute to neuropathology, we will characterize the accumulation of known and novel metabolites in the MPSIIIa mouse brain at early-, mid-, and late-stages of disease and determine whether storage correlates with established pathological indicators.
The second aim of this study will determine whether strategies to reduce the accumulation of primary or secondary metabolites could be used to ameliorate neuropathology. To this end, genetic strategies will be used to reduce heparan sulfate biosynthesis either systemically or in specific cell types in the brain. Pharmacological treatment or intracerebral enzyme administration will be used to reduce the secondary storage of gangliosides or chondroitin sulfate/dermatan sulfate in the MPSIIIa mouse brain, respectively. The significance of this work lies in our ability to identify novel therapeutic targets for treating MPS disease pathology in the brain.
Mucopolysaccharidoses are inherited metabolic disorders, a number of which result from the inability to degrade a glycopolymer known as heparan sulfate, causing its accumulation in the cell and resulting in severe mental retardation. The cause of neuropathology is unclear and may result from the storage of secondary metabolites that have been shown to accumulate in addition to heparan sulfate. This study will characterize the types of secondary metabolites that accumulate in these disorders and will determine whether strategies that reduce the biosynthesis of heparan sulfate or secondary metabolites could be used to treat neuropathology.
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