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An Isoform of Ataxin‐3 Accumulates in the Nucleus of Neuronal Cells in Affected Brain Regions of SCA3 Patients

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado‐Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin‐3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin‐3. This isoform, ataxin‐3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin‐3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin‐3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin‐3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C‐terminal ataxin‐3c antibodies as well as antiataxin‐3 monoclonal antibodies (1H9) and anti‐ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin‐3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin‐3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.