New polyglutamine diseases : from the neuropathologies to the identification of genes responsible for the diseases

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We have studied three patients with pathologically different hereditary spinocerebellar ataxia characterized by 1C2-immunopositive intranuclear inclusions in the affected CNS neurons, namely, polyglutamine diseases. We have also tried to identify the gene responsible for each hereditary disease.(1)We have described a homozygous case of spinocerebellar ataxia type 17 with 48 glutamines. The age of the patient at disease onset was lower than those of heterozygotes with the same CAG-repeat sizes, but the clinical manifestations were rapidly progressive dementia and chorea. Neuronal loss was relatively restricted and most prominent in the Purkinje cell layer and striatum ; however, intranuclear neuronal polyglutamine accumulation was widespread, with a high frequency in the cerebral cortex and striatum.(2)In one of the other two cases, immunoblotting analyses with a monoclonal antibody specific for expanded polyglutamine stretches (1C2) revealed the presence of immunopositive proteins. Furthermore, we identified multiple spots, one of which might be the disease-related protein, using two-dimensional electrophoresis and two-dimensional immunoblotting methods. Further studies are needed to identify the gene responsible for the disease.(3)In the final case, we are trying the same methods to identify the disease-related protein and the causative gene abnormality.