Pathophysiology of Lysosomal Free Sialic Acid Storage Disorders

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DESCRIPTION (provided by applicant): The broad, long-term goal of this proposal is to define mechanisms involved in the pathophysiology of the lysosomal storage disorders Salla disease and infantile sialic acid storage disorder (ISSD) in order to identify novel therapeutic approaches. These disorders are autosomal recessive neurodegenerative diseases associated with progressive impairment of motor function, mental retardation, and ultimately premature death. Enlarged cytoplasmic vacuoles filled with the amino sugar sialic acid define the cellular pathology and a defect in transport of sialic acid across lysosomal membranes has been described. Genetic studies have determined that several mutations in a gene encoding a single protein designated sialin are causative. However, the understanding of the function of sialin, and the physiological effect of genetic alterations is limited. Preliminary data indicate that sialin is a sialic acid transporter that resides in late- endosomal/lysosomal subcellular compartment. Data further indicate that the primary defect in these diseases is a loss of transport activity. A recently developed animal model for these disorders has been generated by the targeted disruption of the mouse sialin gene, but the characterization of these mice is limited. The three specific aims are directed at determining the specific molecular mechanisms underlying the pathology associated with mutations in sialin. The first aim is to describe the developmental and pathological features of sialin deficient mice. The second aim is to determine if loss of silain leads to a defect in the biogenesis or function of the late-endosomal/lysosomal vesicles that normally contain sialin. The third aim is to determine if loss of sialin alters the temporally regulated expression of sialylated glycoproteins or gangliosides. Progress in these aims will lead to an improved understanding of the normal function of this transport protein and insight into the pathophysiology of these diseases.