Research on Lysosomal Storage Disorders

Lysosomes are the compartment within a cell that is responsible for the breakdown of macromolecules into precursors that can be reused as building blocks for proteins and other biomolecules. In many ways, lysosomes can be viewed as the recycling center of the cell. GGC’s Research Division is involved in the investigation of lysosomal storage disorders, a group of inherited diseases caused by defects in enzymes and proteins in lysosomes.
Patients with lysosomal storage disorders are unable to break down certain molecules in the lysosome, causing some tissues and cells to not work properly. Researchers at GGC use zebrafish and cell-based models of these disorders to explore how the loss of lysosomal function leads to the symptoms of the disease. By doing so, they hope to identify new ways to treat patients. Much of the current focus on lysosomal storage disorders centers on the investigation of I-cell disease or mucolipidosis II. This condition is caused by mutations in the GNPTAB gene. This gene encodes an enzyme that adds a carbohydrate tag to newly made hydrolytic enzymes allowing them to target to the lysosome. When the targeting of these enzymes is lost in I-cell disease, the lysosomes of these cells to accumulate storage material because the enzymes are missing. The enzymes are secreted from the cells instead and can interfere with many processes that occur in the extracellular environment that surrounds cells.First clinically recognized by Dr. Jules Leroy, a senior scholar at GGC, this disorder causes profound skeletal abnormalities and other symptoms in affected children but the mechanisms for these symptoms remains poorly understood.
The Steet laboratory in the Research Division at GGC has been leveraging a zebrafish model of I-cell disease to explore the molecular basis of the skeletal and cardiac phenotypes associated with I-cell disease. Using this model, they have identified a role for a secreted protease called cathepsin K in the pathogenesis of I-cell disease and are currently exploring ways to inhibit this enzyme and improve the skeletal and cardiac phenotypes. This zebrafish model has also been used to characterize how missense mutations in the GNPTAB affect the function of the enzyme. 

Other areas of active interest in the Division include: 

  • Investigating whether secreted cathepsins play a role in the frequent lung infections associated with I-cell disease (in collaboration with Rob Tarran at UNC-Chapel Hill) 
  • Developing strategies to improve enzyme replacement therapy for lysosomal storage disorders by increasing receptor recycling (in collaboration with Dwight Koeberl at Duke) 
  • Determining the functional consequences of variants of uncertain significance in the IDUA gene which causes MPSI (in collaboration with Tim Wood and Laura Pollard at GGC) 

One Mother's Story

After a long three-year struggle trying to have children, our son, Charlie, was born on April 18, 2009. He was our miracle...perfect in every way! When Charlie was five days old, our pediatrician called to notify us that one of the numbers from the heel prick test was a bit high. We headed to the hospital that afternoon for more tests. I will never forget the following day. It was cool and crisp - not a cloud in the sky. The next thing I know, our ...

In The News