title: Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS.
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.
authors.affiliation: Academic Neurology Unit, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: Eugene
authors.initials: E
authors.lastname: Halligan
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Baptista
authors.forename: Simon
authors.initials: S
authors.lastname: Allen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.forename: Hazel
authors.initials: H
authors.lastname: Holden
authors.forename: Sian C
authors.initials: SC
authors.lastname: Barber
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Loynes
authors.forename: Clare A
authors.initials: CA
authors.lastname: Wood-Allum
authors.forename: Joseph
authors.initials: J
authors.lastname: Lunec
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000975:Antioxidants; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D051267:NF-E2-Related Factor 2; D009410:Nerve Degeneration / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020218:Response Elements; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C000606290:SOD1 protein, human; D015534:Trans-Activators; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1