Expression Analysis of Ataxin‐7 mRNA and Protein in Human Brain: Evidence for a Widespread Distribution and Focal Protein Accumulation

Spinocerebellar ataxia 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG‐trinucleotide repeat in the coding region of the SCA7 gene. The expansion is translated into an extended polyglutamine stretch in the protein ataxin‐7, a protein of unknown function. By Northern blot analysis expression of ataxin‐7 was detected in numerous regions of human brain and some peripheral tissues. It is unknown, however, if ataxin‐7 is enriched at sites of the SCA7 pathology. We studied the regional and cellular expression pattern of ataxin‐7 at the mRNA level by in situ hybridization histochemistry in normal human brain. Furthermore we used a monoclonal and two polyclonal antibodies raised against the normal ataxin‐7 to establish the distribution of this protein in brain, retina and peripheral organs. At the mRNA level ataxin‐7 was preferentially expressed in neurons; the regional distribution reflected neuronal packing density. Ataxin‐7 immunoreactivity (IR) was similarly widely expressed. In most neurons, ataxin‐7 IR was preferentially localized to the cytoplasmatic compartment although some nuclear ataxin‐7 IR was detected in most neurons. A more intense and more prominently nuclear ataxin‐7 IR was observed in neurons of the pons and the inferior olive, brain regions severly affected by the disease, suggesting that the subcellular localization and abundance of ataxin‐7 is regulated in a regionally specific way. Since neurons displaying more intense and more prominently nuclear ataxin‐7 IR belonged to the class of susceptible cells in SCA7, an enrichment of normal ataxin‐7 in the nuclear compartment may contribute to neurodegeneration. However not all sites of SCA7 pathology displayed a strong cytoplasmatic and nuclear immunoreactivity.