Dysregulation of astrocyte–motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis

Abstract

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.

Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis

“…Specifically, we found elevated glycogen in gray and ventral white matter samples from autopsied patients with ALS, confirmed by histological analyses showing elevated glycogen in both neurons and glia. The increased glycogen in the CNS of SOD1 G93A mice and humans with ALS is consistent with spinal cord gene expression profiling studies from ALS mice and humans that showed elevated glycogen synthase mRNA levels and altered α-glucosidase mRNA (13,19). Indeed, we show here that lysosomal (glycogen degrading) α-glucosidase activity is significantly reduced within the lumbar spinal cord of SOD1 G93A mice in advance of the onset of hindlimb paralysis.…”

“…Indeed, glucose uptake and/or levels within the CNS are significantly diminished in patients with ALS (37), SOD1 G93A mice (32,38), and in WT mice exposed to cerebrospinal fluid (CSF) from patients with ALS (39). Moreover, lactate levels are reduced in spinal cords of SOD1 G93A mice (19), as is the expression of MCT1 (36). Our results extend these findings.…”

“…Interestingly, gene expression studies on laser-captured motor neurons from patients with ALS showed reduced mRNA levels of α-glucosidase, an enzyme that degrades glycogen to glucose (13). Similar studies on lasercaptured astrocytes from SOD1 G93A mice also demonstrated more than twofold increases in glycogen synthase mRNA (19).…”

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…The physiopathological complexity that characterizes ALS [5,6] is one of the most limiting factors for the development of successful therapies. Several works have been conducted targeting one or more of the physiopathological mechanisms linked to the disease, but even if they achieved positive experimental results they have failed to translate into successful human therapies [7,8].…”

“…It is also of relevance that alterations of the SOD1 protein have been reported in sporadic ALS patients [4], increasing the interest of this murine model. Several mechanisms have been implicated as contributors to MN death in ALS, such as glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial defects, impaired axonal transport, and inflammation [5,6]. Nevertheless, positive experimental results targeting some of these abnormalities have failed to translate into successful human trials [7,8].…”