Our interests focus on understanding the molecular mechanism of cellular protein folding, particularly when compromised in association with a disease state. A number of genetic diseases are in fact caused by protein misfolding, or the failure of a mutated protein molecule to assume its native active conformation, generally required for biological activity. In most cases, the genetic mutation responsible for the development of the “misfolding disease” does not compromise the protein's catalytic activity, or the binding site, directly, but rather it hinders the protein's ability to correctly fold into a stable conformation. In the case of non cytoplasmic proteins that fold in the secretory pathways, this partial or complete loss of function could be prevented if the mutated protein could fold in the endoplasmic reticulum (ER) and be trafficked to its physiologic localization where it is generally structurally stable. Particularly, Gaucher's disease is a sphingolipidosis characterized by the impaired activity of the lysosomal enzyme β-glucocerebrosidase (GC) caused by mutations in the GC gene that compromise GC folding in the ER. We seek to use GD as a representative misfolding disorder to discover general therapeutic strategies to enhance the ER folding capacity irrespective of the protein involved in the disease. Such a strategy would allow us identifying small molecules that influence the biological machinery affecting general protein folding and ER export. Such small molecules could ameliorate a wide range of misfolding disease including numerous orphan diseases, for which the development of a protein-specific treatment is not financially feasible owing to the small patient population.

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