Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3 , we performed PCR-based cDNA subtractive hybridization in a cell culture m odel of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endope ptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amylo id precursor protein, the interleukin-1 receptor-related Fos-inducible tran script, and the cytokine stromal cell-derived factor 1 alpha (SDF1 alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased express ion of MMP-2 and amyloid beta -protein (A beta) in pontine neurons containi ng nuclear inclusions. In addition, extracellular A beta -immunoreactive de posits were detected in human SCA3 pons. Furthermore, pontine neurons of SC A3 brains strongly expressed the antiinflammatory interleukin-1 receptor an tagonist, the proinflammatory cytokine interleukin-1 beta, and the proinfla mmatory chemokine SDF1. Finally, increased numbers of reactive astrocytes a nd activated microglial cells were found in SCA3 pons. These results sugges t that inflammatory processes are involved in the pathogenesis of SCA3.