Motor neuron disease (MND) is a neurodegenerative disease in which death of motor neurons leads to progressive failure of the neuromuscular system resulting in death within 2–3 years of symptom onset. Recent work, using murine models expressing mutant forms of the superoxide dismutase 1 (mSOD1) gene and in vitro culture systems, has indicated that astrocytes are likely to contribute to the propagation of motor neuron injury. Using a combination of in vivo and in vitro model systems of SOD1 related ALS, linked back to human biosamples, we aimed to elucidate how astrocyte properties change in the presence of mSOD1. Gene expression profiling of spinal cord astrocytes from presymptomatic mSOD1 mice revealed two striking changes. First, there was evidence of metabolic dysregulation and in particular impairment of the astrocyte lactate transporter, with resultant decrease of spinal cord lactate levels. Second, there was evidence of increased nerve growth factor (NGF) production and dysregulation of the ratio of pro-neurotrophin pro-NGF to mature NGF. Pro-NGF is the precursor of mature NGF and it is biologically active. It has high affinity for p75 receptor and it stimulates p75 expression by neighbouring motor neurons, leading to activation of cell death pathways. Preservation of motor neuron viability could be achieved by increasing lactate provision to motor neurons, depletion of NGF levels, or p75 receptor blockade. These findings are likely to be relevant to human MND, where we have demonstrated increased levels of pro-NGF in CSF and increased expression of the p75 receptor by spinal motor neurons.
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