Research on Lysosomal Storage Disorders

Lysosomes are the compartment within a cell that are 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 actively involved in the investigation of lysosomal storage disorders (LSDs), a group of inherited diseases caused by defects in enzymes and proteins in lysosomes.  Patients with LSDs 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 LSDs centers on the investigation of I-cell disease or mucolipidosis II.  This condition is caused by mutations in GNPTAB.  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 mucolipidosis II, 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.  This disorder causes profound skeletal abnormalities and other symptoms in affected children but the mechanisms for these symptoms remains poorly understood.  The Steet and Flanagan-Steet laboratories in the Research Division at GGC (with the support of a longstanding grant from the National Institutes of Health) has been leveraging a zebrafish model of mucolipidosis II to explore the molecular basis of the skeletal and cardiac phenotypes associated with mucolipidosis II.  Using this model, they have identified a role for a secreted protease called cathepsin K in the pathogenesis of mucolipidosis II and are currently exploring ways to inhibit this enzyme and improve the skeletal and cardiac phenotypes.  They are also studying how the presence of certain types of carbohydrate chains called GAGs can influence cathepsin activity, and the release of cathepsins in the context of other LSDs can be problematic. 

Other areas of active interest in the Division include:

  • Determining the functional consequences of variants of uncertain significance in the IDUA gene which causes MPSI (in collaboration with Laura Pollard at GGC; supported by the National MPS Society)
  • Testing different therapeutic strategies for mucolipidosis II using a feline model (in collaboration with Allison Bradbury at Nationwide Children’s Hospital and Josh Stern at UC Davis)
  • Working closely with advocacy groups such as CureML and the Yash Gandhi Foundation to promote research on LSDs like mucolipidosis II

Meet Makayla Gunn

Makayla was diagnosed with Rett Syndrome in April of 2015 at the age of two. At about 18 months, we noticed she had started some repetitive hand motions, and her pediatrician was a little concerned that she did not have many words. She had learned some sign language, and was saying ‘mama’ and ‘dada’, but that was it. Then she suddenly stopped all of that. At her 2 year old check-up, the pediatrician referred us to BabyNet, SC’s early interve...

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