Lysosomal Storage Disease

About

Description: One in 5000 people, mostly children, suffers from one of the more than 50 lysosomal storage disorders that are characterized by a toxic accumulation of various biomolecules in the tissues and organs.  Effective therapies are limited and mortality is high, often following significant disability caused by a variety of symptoms.  Lysosomal storage disorders may be divided into two broad categories - those that result from defects in normal metabolic processes that lead to an excessive accumulation of biomolecules in cells, and those result from defects in the transport, or trafficking, mechanisms that move biomolecules in and out of cells.  A large fraction of trafficking LSD's are traceable to mutations in membrane-bound ABC transporter proteins, but there is currently little understanding of the transport pathways for most of these diseases; while it is generally known that one of the several ABC proteins initiates the transport function by binding to the cargo molecule, the nature of subsequent acceptors of the cargo molecule along the transport pathway is largely unknown. We are developing novel molecular probes to help elucidate the fundamental components and mechanisms of action along the transport pathways.  Because Niemann-Pick type C (NPC) has a fairly well-understood lipid trafficking defect, it will be used as the platform for proof-of-concept development of the proposed probes.  NPC is an inherited disease with an occurrence of approximately 1:100,000 and is characterized by a lethal accumulation of cholesterol and other lipids in various organs of the body, including the liver, spleen, brain, and bones.  While it is known that NPC results from mutations to either the large, lysosomal membrane-bound NPC1 protein or the smaller soluble lysosomal NPC2 protein, the role that each plays in the defective accumulation of cholesterol in tissue membranes is unknown.  Some studies suggest a NPC1/NPC2 protein-protein interaction, but no firm data exists to confirm the theory.  The lipid trafficking probes being developed will provide the first data to validate, modify, or refute the model. The lipid trafficking probes being developedfor NPC, and analogous probes for other trafficking disorders, offer researchers a valuable tool for better understanding these life-threatening, often fatal, diseases.