title: Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains.
abstract: 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 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-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-1beta, 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.
authors.affiliation: Department of Neurology, University of Bonn, 53105 Bonn, Germany. b.evert@uni-bonn.de
authors.forename: B O
authors.initials: BO
authors.lastname: Evert
authors.forename: I R
authors.initials: IR
authors.lastname: Vogt
authors.forename: C
authors.initials: C
authors.lastname: Kindermann
authors.forename: L
authors.initials: L
authors.lastname: Ozimek
authors.forename: R A
authors.initials: RA
authors.lastname: de Vos
authors.forename: E R
authors.initials: ER
authors.lastname: Brunt
authors.forename: I
authors.initials: I
authors.lastname: Schmitt
authors.forename: T
authors.initials: T
authors.lastname: Klockgether
authors.forename: U
authors.initials: U
authors.lastname: Wüllner
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000067699:Ataxin-3; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053727:Interleukin-18 Receptor alpha Subunit; D017827:Machado-Joseph Disease / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D011149:Pons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D012097:Repressor Proteins; D014157:Transcription Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016564:Amyloid beta-Protein Precursor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C508572:IL18R1 protein, human; C079241:IL1RL1 protein, human; C508573:Il18r1 protein, mouse; C486189:Il1rl1 protein, mouse; C490860:Il1rl2 protein, rat; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053727:Interleukin-18 Receptor alpha Subunit; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D012097:Repressor Proteins; D014157:Transcription Factors; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; C511593:Atxn3 protein, rat; D020778:Matrix Metalloproteinase 2