Altered expression of carbonic anhydrase-related protein XI in neuronal cells expressing mutant ataxin-3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. Microarray analysis revealed a dramatic differential expression of carbonic anhydrase-related protein XI (CA-RPXI/CA11) in the presence or absence of mutant ataxin-3. Therefore, we examined the expression and distribution of all three CA-RPs (CA8, 10, and 11) in human neuronal cells that stably express mutant ataxin-3. Compared with the cells containing normal ataxin-3, protein expression of CA8 and CA11 is significantly increased in human neuroblastoma cells harboring mutant ataxin-3. Semi-quantitative RT-PCR demonstrated that all three CA-RPs exhibited significantly higher transcript levels in neuronal cells expressing mutant ataxin-3. Interestingly, CA11 is distributed not only in the cytoplasm but also within the nuclei of the stably transfected mutant cells when compared with the sole cytoplasmic distribution in cells containing normal ataxin-3. In addition, results from transient transfection assays in SK-N-SH and Neuro2a (N2a) cells also confirmed the nuclear localization of CA11 in the presence of truncated ataxin-3. Most importantly, immunohistochemical staining of the MJD transgenic mouse and post-mortem MJD human brain also revealed that CA11 is highly expressed in both cytoplasm and nuclei of the brain cells. Recruitment of CA11 into nuclear inclusions containing mutant ataxin-3 revealed a possible correlation between CA11 and disease progression. Although the exact function of CA-RPs is still undefined in the central nervous system, our findings suggest that CA-RPs, especially CA11, may play specific roles in the pathogenesis of Machado-Joseph disease.