Brain Advance Access originally published online on May 4, 2005
Brain 2005 128(7):1686-1706; doi:10.1093/brain/awh503
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS
1 Academic Neurology Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield and 2 Genome Instability Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK
Correspondence: Professor Pamela J. Shaw, Academic Neurology Unit, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK E-mail: Pamela.Shaw{at}sheffield.ac.uk
Familial amyotrophic lateral sclerosis (FALS) is caused, in 20% of cases, by mutations in the Cu/Zn superoxide dismutase gene (SOD1). Although motor neuron injury occurs through a toxic gain of function, the precise mechanism(s) remains unclear. Using an established NSC34 cellular model for SOD1-associated FALS, we investigated the effects of mutant SOD1 specifically in cells modelling the vulnerable cell population, the motor neurons, without contamination from non-neuronal cells present in CNS. Using gene expression profiling, 268 transcripts were differentially expressed in the presence of mutant human G93A SOD1. Of these, 197 were decreased, demonstrating that the presence of mutant SOD1 leads to a marked degree of transcriptional repression. Amongst these were a group of antioxidant response element (ARE) genes encoding phase II detoxifying enzymes and antioxidant response proteins (so-called ‘programmed cell life’ genes), the expression of which is regulated by the transcription factor NRF2. We provide evidence that dysregulation of Nrf2 and the ARE, coupled with reduced pentose phosphate pathway activity and decreased generation of NADPH, represent significant and hitherto unrecognized components of the toxic gain of function of mutant SOD1. Other genes of interest significantly altered in the presence of mutant SOD1 include several previously implicated in neurodegeneration, as well as genes involved in protein degradation, the immune response, cell death/survival and the heat shock response. Preliminary studies on isolated motor neurons from SOD1-associated motor neuron disease cases suggest key genes are also differently expressed in the human disease.
Key Words: amyotrophic lateral sclerosis; Nrf2; programmed cell life genes; SOD1
Abbreviations:
Actb = ß-actin; Akr1c13 = aldo-keto reductase family 1, member 13; ALS = amyotrophic lateral sclerosis; AP1 = activator protein 1; ARE = antioxidant response element; Bag3 = Bcl2-associated athanogene 3; Bnip3 = E1B 19 kDa/Bcl2 binding protein Nip3; B2m = ß2-microglobulin; Ccl2 = chemokine (C-C motif) ligand 2; Cox4A = cytochrome c oxidase subunit 4; Ddc = dopa decarboxylase; Erk = extracellular signal-regulated kinase; c-Fos = FBJ osteosarcoma oncogene; Gadd45a = growth arrest and DNA damage inducible 45 a; Gsn = gelsolin; GST = glutathione S-transferase; Gsta3 = glutathione S-transferase alpha 3; Gstm1/2 = glutathione S-transferase mu 1/2; G6pd = glucose-6-phosphate dehydrogenase; Hspa1b/4 = heat shock protein 1b/4; Idb2 = inhibitor of DNA binding 2; Jun = v-jun avian sarcoma virus 17 oncogene homologue; Lmp7 = 20s proteasome ß5 inducible subunit; Ltb4dh = leukotriene B4 12-hydroxydehydrogenase; c-Myc = myelocytomatosis oncogene; ß-NF = ß-napthoflavone; Nrf2 = nuclear factor erythroid 2-like 2; PA28
/ß = proteasome activator 28 /ß subunits; PA200 = proteasome activator 200 kDa; Pdcd6ip = programmed cell death 6 interacting protein; PDTC = pyrrolidinedithiocarbamate; 6Pgd = 6-phosphogluconate dehydrogenase; Prdx3 = peroxiredoxin 3; Prdx4 = peroxiredoxin 4; Rgs2 = regulator of G-protein signalling 2; Scg2 = secretogranin II; Smn = survival motor neuron; SOD1 = Cu/Zn superoxide dismutase; S100a6 = calcyclin; t-BHQ = t-butylhydroquinone; Vegf = vascular endothelial growth factor
Received May 26, 2004. Revised March 9, 2005. Accepted March 15, 2005.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Bergemalm, K. Forsberg, P. A. Jonsson, K. S. Graffmo, T. Brannstrom, P. M. Andersen, H. Antti, and S. L. Marklund Changes in the Spinal Cord Proteome of an Amyotrophic Lateral Sclerosis Murine Model Determined by Differential In-gel Electrophoresis Mol. Cell. Proteomics, June 1, 2009; 8(6): 1306 - 1317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Simpson, O. Hosny, S. B. Wharton, P. R. Heath, H. Holden, M. S. Fernando, F. Matthews, G. Forster, J. T. O'Brien, R. Barber, et al. Microarray RNA Expression Analysis of Cerebral White Matter Lesions Reveals Changes in Multiple Functional Pathways Stroke, February 1, 2009; 40(2): 369 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pitzer, C. Kruger, C. Plaas, F. Kirsch, T. Dittgen, R. Muller, R. Laage, S. Kastner, S. Suess, R. Spoelgen, et al. Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis Brain, December 1, 2008; 131(12): 3335 - 3347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nishitoh, H. Kadowaki, A. Nagai, T. Maruyama, T. Yokota, H. Fukutomi, T. Noguchi, A. Matsuzawa, K. Takeda, and H. Ichijo ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1 Genes & Dev., June 1, 2008; 22(11): 1451 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Ferraiuolo, P. R. Heath, H. Holden, P. Kasher, J. Kirby, and P. J. Shaw Microarray Analysis of the Cellular Pathways Involved in the Adaptation to and Progression of Motor Neuron Injury in the SOD1 G93A Mouse Model of Familial ALS J. Neurosci., August 22, 2007; 27(34): 9201 - 9219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pehar, M. R. Vargas, K. M. Robinson, P. Cassina, P. J. Diaz-Amarilla, T. M. Hagen, R. Radi, L. Barbeito, and J. S. Beckman Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis J. Neurosci., July 18, 2007; 27(29): 7777 - 7785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zona, M. Pieri, and I. Carunchio Voltage-Dependent Sodium Channels in Spinal Cord Motor Neurons Display Rapid Recovery From Fast Inactivation in a Mouse Model of Amyotrophic Lateral Sclerosis J Neurophysiol, December 1, 2006; 96(6): 3314 - 3322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Wood-Allum, S. C. Barber, J. Kirby, P. Heath, H. Holden, R. Mead, A. Higginbottom, S. Allen, T. Beaujeux, S. E. Alexson, et al. Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen Brain, July 1, 2006; 129(7): 1693 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhai, H. Lin, R. Canete-Soler, and W. W. Schlaepfer HoxB2 binds mutant SOD1 and is altered in transgenic model of ALS Hum. Mol. Genet., September 15, 2005; 14(18): 2629 - 2640. [Abstract] [Full Text] [PDF]
|
|