The molecular genetics of spinocerebellar degenerations

Spinocerebellar ataxia type-1 (SCA1) is a neurodegenerative disorder characterized by progressive loss of motor coordination and impairment of brain stem function. The most prominent neuropathologic findings include loss of cerebellar Purkinje cells and inferior olivary neurons. SC Al is caused by expansion of a CAG trinucleotide repeat which encodes glutamine in a novel protein ataxin-1. This mutational mechanism is shared by many other dominnntly inherited neurodegenerative disorders. We and others proposed that the proteins with expanded polyglutamine tracts acquire new functions or properties which render them toxic to selective neurons. To test their hypothesis, we introduced the human mutation into mice using an SCA1 cDNA with 82 repeats and a Purkinje cell specific promoter. Transgenic mice with the wild type cDNA are normal but mice with the expanded allele developed ataxia and Purkinje cell degeneration. Care lui characterization of the mice both at the behavioral and neuropathological levels revealed that the clinical phenotype develops before there is any notable neuronal loss suggesting that mutant ataxin-1 leads to dysfunction of Purkinje cells prior to the onset of degeneration. Using the yeast two hybrid system and biochemical approaches, we focused on identifying proteins which preferentially interact with mutant ataxin-1. Data summarizing these studies will be presented.