Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder in which motor neurons in the spinal cord and motor cortex degenerate. Although the majority of ALS cases are sporadic, mutations in Cu-Zn superoxide dismutase-1 (SOD1) are causative for 10-20% of familial ALS (fALS), and recent findings show that a hexanucleotide repeat expansion in the C9ORF72 gene may account for >30% of fALS cases in Europe. SOD1(G93A) transgenic mice have a phenotype and pathology similar to human ALS. In both ALS patients and SOD1(G93A) mice, the first pathological features of disease manifest at the neuromuscular junction, where significant denervation occurs prior to motor neuron degeneration. Strategies aimed at preventing or delaying denervation may therefore be of benefit in ALS. In this study, we show that Nogo-A levels increase in muscle fibres of SOD1(G93A) mice along with the elevation of markers of neuromuscular dysfunction (CHRNA1/MUSK). Symptomatic treatment of SOD1(G93A) mice from 70 days of age with an anti-Nogo-A antibody (GSK577548) significantly improves hindlimb muscle innervation at 90 days, a late symptomatic stage of disease, resulting in increased muscle force and motor unit survival and a significant increase in motor neuron survival. However, not all aspects of this improvement in anti-Nogo-A antibody-treated SOD1(G93A) mice were maintained at end-stage disease. These results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo-A may be a disease-modifying approach in ALS.

ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

“…sAPP-α binds to unphosphorlyated CRMP2 which may help maintain CRMP2 in an non-phosphorylated state and thus aid in the stabilization of the neuronal cytoskeleton. Neutralization strategies using antibodies directed toward NRP1 (Venkova et al, 2014) or NOGO-A (Bros-Facer et al, 2014) have the ability to inhibit these signaling pathways, probably by preventing phosphorylation of the appropriate CRMPs, and thus enhancing neuronal cytoskeleton stabilization. Fasudil, a RhoA-kinase inhibitor, can be administered to prevent EPHA4 function by inhibiting the activation of downstream mediators that usually lead to the destabilization of the neuronal cytoskeleton.…”

“…NMJ destabilization by NOGO-A is consistent with the fact that NOGO-A signaling has been linked to synaptic plasticity and stability in hippocampal neurons (Peng et al, 2011) and in the adult cerebral cortex (Akbik et al, 2013). A recent study has illustrated the potential of anti-NOGO-A antibodies in significantly improving neuromuscular function even when administered to ALS mice in the symptomatic stages of the disease (Bros-Facer et al, 2014). Currently a Phase II trial is underway using anti-NOGO-A antibodies (GSK; Ozanezumab) in an effort to neutralize NOGO-A function in ALS patients (ClinicalTrials.gov: NCT01753076), with primary results due in May 2015.…”

Dysfunctional mitochondrial Ca2+ handling in mutant SOD1 mouse models of fALS: integration of findings from motor neuron somata and motor terminals

“…Skeletal muscles in mutant SOD1 mice evidence signs of hypermetabolism and oxidative stress even at asymptomatic stages of disease (reviewed in Cozzolino and Carri, 2012), and increase expression of Nogo-A, which inhibits formation of neuromuscular junctions (Bros-Facer et al, 2014). …”

ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers

“…Mutations in the superoxide dismutase 1 gene (SOD1) account for 10–20% of all fALS cases. Recently, a hexanucleotide repeat expansion in the C9ORF72 gene was found to explain more than 50% of fALS cases [3, 4]. It has been shown that overexpression of the mutant human SOD1 gene in mice reproduces the ALS phenotype observed in humans [5].…”