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The Journal of Neuroscience, August 1, 2001, 21(15):5389-5396

Inflammatory Genes Are Upregulated in Expanded Ataxin-3-Expressing Cell Lines and Spinocerebellar Ataxia Type 3 Brains

Bernd O. Evert¹, Ina R. Vogt¹, Claudia Kindermann¹, Lucia Ozimek¹, Rob A. I. de Vos², Ewout R. P. Brunt³, Ina Schmitt¹, Thomas Klockgether¹, and Ullrich Wüllner¹

¹ Department of Neurology, University of Bonn, 53105 Bonn, Germany, ² Laboratorium Pathologie Oost Nederland, 7512 AD Enschede, The Netherlands, and ³ Department of Neurology, University of Groningen, 9713 AW Groningen, The Netherlands

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 model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1 (SDF1). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid -protein (A) in pontine neurons containing nuclear inclusions. In addition, extracellular A-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.

Key words: spinocerebellar ataxia 3; polyglutamine disease; neurodegeneration; cell death; inflammation; gene expression; ataxin-3

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155389-08$05.00/0

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