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 codin g region of the SCA7 gene. The expansion is translated into an extended pol yglutamine stretch in the protein ataxin-7, a protein of unknown function. By Northern blot analysis expression of ataxin-7 was detected in numerous r egions 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 regi onal and cellular expression pattern of ataxin-7 at the mRNA level by in si tu 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 perip heral organs. At the mRNA level ataxin-7 was preferentially expressed in ne urons; the regional distribution reflected neuronal packing density. Ataxin -7 immunoreactivity (IR) was similarly widely expressed. In most neurons, a taxin-7 IR was preferentially localized to the cytoplasmatic compartment al though some nuclear ataxin-7 IR was detected in most neurons. A more intens e and more prominently nuclear ataxin-7 IR was observed in neurons of the p ens and the inferior olive, brain regions severly affected by the disease, suggesting that the subcellular localization and abundance of ataxin-7 is r egulated in a regionally specific way. Since neurons displaying more intens e and more prominently nuclear ataxin-7 IR belonged to the class of suscept ible cells in SCA7, an enrichment of normal ataxin-7 in the nuclear compart ment may contribute to neurodegeneration. However not all sites of SCA7 pat hology displayed a strong cytoplasmatic and nuclear immunoreactivity.