Modulation of Cellular Clearance in Lysosomal Storage Disorders

Lysosomal storage diseases (LSDs) are inherited disorders affecting 1/5000 people. The symptoms of LSDs are progressive and, depending on the particular disorder, can be mild to severe, affecting several tissues and organs, particularly the brain. LSDs are the commonest cause of pediatric neurodegenerative disease. The primary defect of LSDs is a defective function of the function of the lysosome, the cellular organelle that is dedicated to the degradation and recycling of the products of cellular metabolism. Therefore, LSDs are characterized by the accumulation of storage material, due to defective lysosomal degradation and impaired cellular clearance, in both the central nervous system and in visceral tissues. There are no effective cures for LSDs, in particular for the neurologic and bone abnormalities. Recently, we discovered a gene, TFEB, which controls lysosomal function. Enhancement of the activity of this gene results in efficient cellular clearance in cells from LSD patients and in murine models of LSDs. This project aims at providing proof-of-principle studies for the use of the modulation of TFEB activity as a new strategy to treat LSDs. If successful these studies will potentially inpact on the treatment of common neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, which are also associated to the accumulation of storage material in the cells.