The neuronal ceroid lipofuscinoses (NCL) comprise a group of poorly understood inherited neurodegenerative diseases of children and adults. Although canine and ovine models of this disease are available, they are not economical to maintain, difficult to study genetically, and not easily manipulated experimentally. Two mouse models of NCL have been discovered. Both develop severe neurological disease; both have numerous neuronal cytoplasmic autoflourescent inclusions. Ultrastructurally these inclusions consist of stacked membranes identical to those found in the canine model of NCL and similar to inclusions considered diagnostic of human forms of the disease. One of these mouse mutants, juvenile bare (jb), has been mapped to the proximal part of Chromosome 7; the genetic linkage of the second mutant, motor neuron degeneration (Mnd), will be established, and candidate genes for both mouse diseases will be sought. These mutants will be studied to characterize the progression of lesions in affected organs, particularly the brain, during the life span. Early diagnostic lesions will be sought. The basis of the biochemical defect will be analyzed by isolating and sequencing the stored lysosomal protein(s) and searching for abnormal lysosomal enzymes. A search for other models of NCL will be conducted among the dozens of known mouse mutants with blindness, seizures, diffuse neuronal degeneration and known lysosomal disorders. Finally, the mutant models will be made available to other investigators. It is hoped that studies of these models will provide important insights into the devastating pathogenesis of Batten disease.
