The long-term objective of the work proposed is to understand the molecular basis of neuronal ceroid lipofuscinosis (NCL), the most common neurodegenerative disorder of childhood. NCL refers to a group of inherited disorders characterized by loss of vision, seizures, and progressive mental deterioration. The hallmark of these diseases is the accumulation of autofluorescent lipopigments in storage bodies found in the brain and peripheral tissues. The biochemical basis of NCL remains unknown and there is no treatment effective in delaying or preventing the progression of this fatal disorder. The applicant and her colleagues recently succeeded in isolating the gene for juvenile NCL, CLN3. This gene encodes a protein of as yet unknown function. It is the goal of the application to establish the normal function of this protein. The investigators will study the pattern of expression and cellular localization of CLN3, which may identify specific subcellular organelles or biochemical pathways as important in the pathogenesis of JNCL. They will also identify proteins that interact with CLN3, which may implicate specific protein-protein interactions along these pathways. Finally, they will insertionally inactivate the mouse CLN3 gene, which may reveal clues as to the role of CLN3 in development. These knock-out mice may prove valuable for studying the mechanism of the disease and for evaluating new therapies. The combined results of these studies should provide the basis for formulating hypotheses concerning the normal function of CLN3, and provide a better understanding of the pathogenesis and potential treatment of the disease.
