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Brain Advance Access published online on May 4, 2005
Brain, doi:10.1093/brain/awh503
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received May 26, 2004
Revised March 9, 2005
Accepted March 15, 2005

Article

Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS

Janine Kirby 1, Eugene Halligan 2, Melisa J. Baptista 1, Simon Allen 1, Paul R. Heath 1, Hazel Holden 1, Sian C. Barber 1, Catherine A. Loynes 1, Clare A. Wood-Allum 1, Joseph Lunec 2, and Pamela J. Shaw 3*

1 Academic Neurology Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield, UK
2 Genome Instability Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK
3 Academic Neurology Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield

* To whom correspondence should be addressed.
Pamela J. Shaw, E-mail: Pamela.Shaw{at}sheffield.ac.uk


  Abstract

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.

Keywords: amyotrophic lateral sclerosis; Nrf2; programmed cell life genes; SOD1.
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