Mutations in transporter protein shed light on neurodegenerative disorders

Researchers at Stanford University have made new discoveries that shed light on two inherited neurodegenerative disorders that are caused by inability of the body to transport sialic acid out of cellular compartments. The findings focus on how different mutations in one transporter molecule can cause a wide spectrum of symptoms in Salla Disease and infantile sialic acid storage disease (ISSD).

The research appears as the “Paper of the Week” in the January 14 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

The free sialic acid storage diseases are a range of rare, autosomal recessive, neurodegenerative disorders that result from the accumulation of sialic acid within lysosomes. There are two forms of the disease–Salla Disease, the milder form, and the more severe infantile sialic acid storage disease (ISSD). “Clinically, these diseases consist of a spectrum,” notes Dr. Richard J. Reimer of Stanford University. “In the severe phenotype infants are born with dysmorphic features, enlarged internal organs and die within a few months. With the milder disease the affected individuals have physical and mental developmental delay, but can live to adulthood.”

In Salla Disease and ISSD, the amino sugar sialic acid accumulates in lysosomes, the cellular compartments that are responsible for degrading macromolecules. “Sialic acid is part of a number of proteins and normally it is removed from proteins as they are degraded in lysosomes,” explains Dr. Reimer. “The free sialic acid is then released into the cytoplasm of the cell so that it can be reincorporated in to newly synthesized proteins. In Salla Disease and ISSD, the sialic acid is removed from the protein, but it is not released from the lysosome.”

Genetic studies have shown that mutations in a single gene encoding a protein called sialin are responsible for both diseases. “The milder form is associated with a single mutation and is most common in a region in northern Finland,” says Dr. Reimer. “The more severe form does not appear to have a regional or ethnic predilection and can be caused by any of several different mutations. To date a total of 18 mutations have been identified in addition to the Finnish mutation.”

To better understand how mutations in sialin cause the two diseases, Dr. Reimer and his colleagues at Stanford altered part of the sialin molecule, causing it to be expressed on the surface of cells rather than inside lysosomes. In doing this, the researchers were able to easily compare the sialic acid transport ability of normal versus mutated versions of sialin. Using this approach, they proved that sialin is responsible for transporting sialic acid out of the lysosome.

Dr. Reimer and his colleagues also evaluated the impact of sialin’s identified mutations on sialic acid export and discovered a direct correlation between the degree of transport activity lost and the severity of the clinical phenotype. “In the more common and milder form of the disease we found that the mutant proteins work, but not as well. Our findings suggest that for the milder form of the disease a functional protein is still produced, but with reduced activity. From the work of others we know that carriers are asymptomatic even with a 50 percent reduction in sialic acid transport activity. This suggests that for the milder form of the disease increasing the level of expression or stability of the protein could be one way to treat the disease,” concludes Dr. Reimer.