Juvenile ceroid-lipofuscinosis (Batten disease, CLN3) is one of the most common hereditary neurodegenerative disorders. It is inherited as an autosomal-recessive trait. Blindness due to retinal degeneration is usually the first clinical symptom, with complete vision loss occurring between the ages of 5 and 7 years. Subsequently, affected individuals develop seizures, and undergo psychomotor and cognitive deterioration to a vegetative state. Death usually occurs in the late teenage years to the twenties. The severe and progressive nature of this disease results in enormous medical, financial, and emotional burdens on families with afflicted children. Little is known regarding the etiology of Batten disease, and no effective treatments have been developed. A distinctive biochemical feature of this disorder is a massive intracellular accumulation of autofluorescent lysosomal storage bodies in most tissues. The subunit c protein of mitochondrial ATP synthase is a major constituent of the storage bodies. The overall goals of the proposed research are to determine the molecular mechanisms responsible for the lysosomal storage of the subunit c protein, and to develop treatments that will prevent or slow the progressive neuronal degeneration that leads to blindness and cognitive decline. To accomplish these goals, experiments will be conducted to achieve the following specific aims: (1) complete phenotypic characterization of a mouse """"""""gene knock-out"""""""" model for juvenile ceroid-lipofuscinosis; (2) determine whether carnitine supplements can slow disease progression in mice in which the CLN3 gene has been inactivated (knocked out); (3) evaluate the potential of neuroprotectants to prevent neural degeneration in mice in which the CLN3 gene has been knocked out; (4) purify and characterize the CLN3 protein; and (5) determine whether the rates of subunit c protein synthesis and/or degradation are altered in juvenile ceroid-lipofuscinosis and in tissues of CLN3 knock-out mice.
