Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3.
Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation of inflammatory genes in transgenic SCA3 cell lines and human SCA3 pontine neurons. We report here a complex pattern of transcriptional changes by microarray gene expression profiling and Northern blot analysis in a SCA3 cell model. Twenty-three differentially expressed genes involved in inflammatory reactions, nuclear transcription, and cell surface-associated processes were identified. The identified corresponding proteins were analyzed by immunohistochemistry in human disease and control brain tissue to evaluate their implication in SCA3 pathogenesis. In addition to several inflammatory mediators upregulated in mutant ataxin-3 expressing cell lines and pontine neurons of SCA3 patients, we identified a profound repression of genes encoding cell surface-associated proteins in cells overexpressing normal ataxin-3. Correspondingly, these genes were upregulated in mutant ataxin-3 expressing cell lines and in pontine neurons of SCA3 patients. These findings identify for the first time target genes transcriptionally regulated by normal ataxin-3 and support the hypothesis that both loss of normal ataxin-3 and gain of function through protein-protein interacting properties of mutant ataxin-3 contribute to SCA3 pathogenesis.
Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. b.evert@uni-bonn.de
Bernd O
BO
Evert
Ina R
IR
Vogt
Ana M
AM
Vieira-Saecker
Lucia
L
Ozimek
Rob A I
RA
de Vos
Ewout R P
ER
Brunt
Thomas
T
Klockgether
Ullrich
U
Wüllner
D000818:Animals; D000067699:Ataxin-3; D001345:Autoradiography; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020224:Expressed Sequence Tags; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D005971:Glutamates / Q000235:genetics; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D050856:Interferon Regulatory Factor-1; D017827:Machado-Joseph Disease / Q000378:metabolism / Q000473:pathology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D008875:Middle Aged; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes; D015854:Up-Regulation / Q000235:genetics
C490341:ANP32B protein, human; C490338:Anp32a protein, rat; D019208:Brain-Derived Neurotrophic Factor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005971:Glutamates; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494259:Irf1 protein, rat; D018832:Molecular Chaperones; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C085047:PSME1 protein, human; D010750:Phosphoproteins; D011506:Proteins; C490050:Psme1 protein, rat; C490052:Psme2 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat; D046988:Proteasome Endopeptidase Complex