Neurodegenerative disorders comprise a broad class of diseases affecting brain and mind. While several genetic lesions that trigger such diseases are now known, the subsequent steps in pathogenesis remain poorly understood. However, a convergence of genetic data from both humans and mice suggests that the number of distinct mechanisms may be relatively small. A detailed genetic analysis of a newly recognized neurodegenerative pathway may thus provide new insight into the pathogenic mechanisms and genetic liability to disease. A partial loss of function mutation (vibrator) of the phosphatidylinositol transfer protein alpha (PITPalpha) gene in mouse results in progressive tremor and degeneration of brain stem and spinal cord neurons, typically ending in juvenile death. The mutation arose by a transposon inserting into an intron of the gene. The severity of the resulting syndrome varies with genetic strain background, and we have mapped a major modifying locus, Mvb1, to mouse chromosome 19. 1. This proposal uses simple genetic crosses to test competing hypothesis about the mechanisms by which Mvb1 suppresses vb and to test the hypothesis that vibrator can also be suppressed by mechanisms similar to those for the related Drosophila gene, rdgB. 2. This proposal uses a positional complementation cloning approach to identify the Mvb1 gene. Molecular cloning of MVB1 will allow the ultimate test of hypotheses concerning the mechanism of suppression in a neurodegenerative disorder. Cloning or Mvb1 will further provide a demonstration of the ability to identify causative strain differences that underlie genetic modifiers in the absence of either parental chromosomes or multiple alleles. 3. This proposal uses a genetic titration of PITPalpha function in combination with simple histological and biochemical assays to test hypotheses about the underlying cellular events in vibrator-triggered disease and to test the hypotheses that these include known events in the pathogenesis of human neurodegenerative diseases.
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