Although neurodegenerative disorders are prevalent in the aging human population, the molecular mechanisms underlying these diseases are not well understood. Many human neurodegenerative disorders have genetic components and similarly, several mutant mouse strains exist that have abnormal neuronal death. The analysis of mouse strains with spontaneous mutations that result in the death of specific terminally differentiated neurons provides a way to identify novel molecules necessary for the survival of neurons in the adult brain. Several mouse mutations exist that result in the abnormal death of embryonic or early postnatal neurons. In contrast, our studies of mice homozygous for the spontaneous mutation sticky (sti), have shown that this mutation causes neuron loss in adult mice accompanied by locomotor defects. Further, like human disorders which affect the survival of particular classes of neurons, specific types of neurons die in sti mutant mice: Distinct subsets of sti/sti Purkinje cells are lost at 1-2 months followed by the loss of rostral granule cells. To begin the identification of the molecular lesion in sti mutant mice, we have fine mapped the mutation to a 0.17 cM interval on Chromosome 8 and have generated a genomic contig across the region. Further, by examination of mouse sequence from this area and the corresponding human sequence on Chromosome 16, we have identified several candidates for the sti gene that reside within the minimal interval of this gene. In addition, we have identified a monogenic genetic suppressor of sti-mediated neurodegeneration on proximal Chromosome 2. As the first steps in understanding the role of the sti gene in neuron survival, this application outlines our strategy to identify both the sti gene and its modifier gene, Stim. The results of these experiments will contribute significantly to our knowledge of the molecules necessary for survival of specific neurons in the adult brain. The identification of the Stim modifier gene will give us not only additional insight into the molecular action of the sti gene product, but will advance our understanding of genes regulating the phenotypic heterogeneity often observed in human neurodegenerative disorders.
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