PROPOSED RAT MODEL OF OLIVOPONTOCEREBELLAR ATROPHY

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Olivopontocerebellar atrophy (OPCA) is one entity in a diverse group of familial, progressive, neurodegenerative disorders in man and animals that is characterized by variable atrophy of the cerebellum, basis pontis, and olivary nuclei. The spinal cord is affected in cases that are grouped with the spinocerebellar ataxias (SCA). Various basal nuclei are involved in forms of OPCA known as multiple system atrophy. Spontaneous and inherited forms of the disease exist. Modes of inheritance include autosomal dominant with anticipation, autosomal recessive, and X-linked recessive transmission (2, 3, 10, 11). Mutations causing SCA have been found at seven different loci in man (2, 15, 17, 18, 20, 22, 77) and include CAG repeat expansion in SCA-1, -3, and -7 (15, 17, 77). Studies to identify mutations in other forms of OPCA are underway. Various animal models (25, 29, 30, 31, 32) mimic human disease. An inbred line of Berlin Druckrey IV (BD IV) rats with early onset of pelvic limb ataxia has been identified as a possible new animal model for OPCA, and is the focus of this study. The affected rats exhibit signs of cerebellar disease and show neuronal loss in the olivary nuclei. Swollen axons in the brainstem and spinal cord contain markedly increased amounts of floccular material suggestive of tangled microtubules, such as those described in human disease (38, 40), or exaggerated amounts of polyribosomes. Pedigrees of these rats have been established by cross-intercross and cross-backcross breeding schemes. The DNA from second generation progeny will be examined for DNA length polymorphism with the polymerase chain reaction (PCR)(57). Linkage analysis (55) will be used to select and map the polymorphic region associated with the mutant phenotype. YAC clones and chromosomal walking(60) will identify the target sequence for study. Selected genes will be sequenced and compared with those in normal BD IV rats to identify the mutation. Morphologic studies will help discern the mechanism of mutation pathogenesis. This study will identify the underlying genetic regions involved in the inheritance of this disorder in BD IV rats and a potential natural animal model for OPCA, and thereby provide a candidate gene for evaluation in man. In addition, insights gained may add to knowledge of pathogenesis of OPCA and related disorders in man.