Enter Your Search:
Results 1-1 (1)
Go to page number:
Select a Filter Below
Barber, Sian (1)
Ferraiuolo, Laura (1)
Greenald, David (1)
Heath, Paul R. (1)
Higginbottom, Adrian (1)
Kirby, Janine (1)
Shaw, Pamela J. (1)
Year of Publication
Did you mean:
Dysregulation of astrocyte–motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis
Heath, Paul R.
Shaw, Pamela J.
Amyotrophic lateral sclerosis is a neurodegenerative disease in which death of motoneurons leads to progressive failure of the neuromuscular system resulting in death frequently within 2–3 years of symptom onset. Focal onset and propagation of the disease symptoms to contiguous motoneuron groups is a striking feature of the human disease progression. Recent work, using mutant superoxide dismutase 1 murine models and in vitro culture systems has indicated that astrocytes are likely to contribute to the propagation of motoneuron injury and disease progression. However, the basis of this astrocyte toxicity and/or failure of motoneuron support has remained uncertain. Using a combination of in vivo and in vitro model systems of superoxide dismutase 1-related amyotrophic lateral sclerosis, linked back to human biosamples, we set out to elucidate how astrocyte properties change in the presence of mutant superoxide dismutase 1 to contribute to motoneuron injury. Gene expression profiling of spinal cord astrocytes from presymptomatic transgenic mice expressing mutant superoxide dismutase 1 revealed two striking changes. First, there was evidence of metabolic dysregulation and, in particular, impairment of the astrocyte lactate efflux transporter, with resultant decrease of spinal cord lactate levels. Second, there was evidence of increased nerve growth factor production and dysregulation of the ratio of pro-nerve growth factor to mature nerve growth factor, favouring p75 receptor expression and activation by neighbouring motoneurons. Functional in vitro studies showed that astrocytes expressing mutant superoxide dismutase 1 are toxic to normal motoneurons. We provide evidence that reduced metabolic support from lactate release and activation of pro-nerve growth factor-p75 receptor signalling are key components of this toxicity. Preservation of motoneuron viability could be achieved by increasing lactate provision to motoneurons, depletion of increased pro-nerve growth factor levels or p75 receptor blockade. These findings are likely to be relevant to human amyotrophic lateral sclerosis, where we have demonstrated increased levels of pro-nerve growth factor in cerebrospinal fluid and increased expression of the p75 receptor by spinal motoneurons. Taken together, these data confirm that altered properties of astrocytes are likely to play a crucial role in the propagation of motoneuron injury in superoxide dismutase 1-related amyotrophic lateral sclerosis and indicate that manipulation of the energy supply to motoneurons as well as inhibition of p75 receptor signalling may represent valuable neuroprotective strategies.
amyotrophic lateral sclerosis; astrocytes; microarray; lactate; nerve growth factor
Results 1-1 (1)
Go to page number:
Remove citation from clipboard
Add citation to clipboard
This will clear all selections from your clipboard. Do you wish proceed?
Clipboard is full! Please remove an item and try again.
PubMed Central Canada is a service of the
Canadian Institutes of Health Research
(CIHR) working in partnership with the National Research Council's
national science library
in cooperation with the
National Center for Biotechnology Information
U.S. National Library of Medicine
(NCBI/NLM). It includes content provided to the
PubMed Central International archive
by participating publishers.