Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1.
Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons. Mutations in the Cu/Zn superoxide dismutase (SOD1) are found in approximately 20% of patients with familial ALS. Mutant SOD1 causes motor neuron death through an acquired toxic property. Although the molecular mechanism underlying this toxic gain-of-function remains unknown, evidence support the role of mutant SOD1 expression in nonneuronal cells in shaping motor neuron degeneration. We have previously found that in contrast to nontransgenic cells, SOD1(G93A)-expressing astrocytes induced apoptosis of cocultured motor neurons. This prompted us to investigate whether the effect on motor neuron survival was related to a change in the gene expression profile. Through high-density oligonucleotide microarrays, we found changes in the expression of genes involved in transcription, signaling, cell proliferation, extracellular matrix synthesis, response to stress, and steroid and lipid metabolism. The most up-regulated gene was decorin (Dcn), a small multifunctional extracellular proteoglycan. Down-regulated genes included the insulin-like growth factor-1 receptor (Igf-1r) and the RNA binding protein ROD1. Rod1 was also found down-regulated in purified motor neurons expressing SOD1(G93A). Changes in the expression of Dcn, Igf-1r, and Rod1 were found in the spinal cord of asymptomatic animals, suggesting these changes occur before overt neuronal degeneration and potentially influence astrocyte-motor neuron interaction in the course of the disease. The astrocyte-specific gene expression profile might contribute to the identification of possible candidates for cell type-specific therapies in ALS.
Vargas
Marcelo R
MR
Departamento de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
Pehar
Mariana
M
Díaz-Amarilla
Pablo J
PJ
Beckman
Joseph S
JS
Barbeito
Luis
L
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D038941:Polypyrimidine Tract-Binding Protein; D011509:Proteoglycans / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; C118823:PTBP3 protein, human; D011509:Proteoglycans; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D017526:Receptor, IGF Type 1