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.

Mitochondrial Superoxide Production and Nuclear Factor Erythroid 2-Related Factor 2 Activation in p75 Neurotrophin Receptor-Induced Motor Neuron Apoptosis

“…A similar reduction in Nrf2 expression was previously observed in a motor neuron-like NSC34 cell line transfected with a mutant SOD1 expression vector and in motor neurons from SOD1-associated familial ALS cases (Kirby et al, 2005). This reduction in Nrf2 expression could explain the increased susceptibility of SOD1 G93A motor neurons not only to NGF but also to Fasmediated apoptosis, which also involves ROS and RNS production (Raoul et al, 2002).…”

Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis

“…Gene expression profiling of the widely used NSC34 cellular model of SOD1-related FALS identified a marked degree of transcriptional repression in the presence of the SOD1 G93A mutation (Kirby et al 2005). These repressed genes included a group of antioxidant response (ARE) genes or "programmed cell life" genes that are regulated by the Nrf2 transcription factor (Figure 1).…”

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

“…Pathologically, it is characterized by progressive, selective motor neuron loss in the brain and spinal cord [2,3] . Mutations in copper/zinc superoxide dismutase (SOD1) account for ~20% of familial cases of ALS [3,4] . In this study, mice overexpressing the G93A mutation of SOD1 were used to model ALS.…”

“…Our previous study and those of others have shown the accumulation of autophagic vacuoles in the spinal cord of SOD1 G93A mice and ALS patients, suggesting a role of autophagy in the pathogenesis of ALS [5,10] . We further reported that targeting autophagy with rapamycin, a classic autophagy activator, significantly exacerbates motor neuron loss and fails to Neurosci Bull August 1, 2015, 31 (4): [459][460][461][462][463][464][465][466][467][468] 460 remove the abnormal mutant SOD1 aggregates, raising the possibility of autophagic flux defects in SOD1 G93A mice [11] .…”