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Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive distal axonopathy that precedes actual motor neuron death. Triggers for neuromuscular junction degeneration remain to be determined, but the axon repulsion factor semaphorin 3A (Sema3A), which is derived from terminal Schwann cells, is a plausible candidate. This study examines the hypothesis that Sema3A signaling through its motor neuron neuropilin-1 (NRP1) receptor triggers distal axonopathy and muscle denervation in the SOD1 mouse model of ALS. Neuropilin-1 was found to be expressed in axonal terminals at the mouse neuromuscular junction in vivo and in NSC-34 motor neuron-like cells in vitro. In differentiated NSC-34 cells, an anti-NRP1 antibody that selectively blocks Sema3A binding to NRP1 prevented Sema3A-induced growth cone collapse. Furthermore, intraperitoneal injections of anti-NRP1 antibody administered twice weekly from age 40 days significantly delayed and even temporarily reversed motor functional decline while prolonging the life span of SOD1 mice. Histologic evaluation at 90 and 125 days revealed that anti-NRP1 antibody reduced neuromuscular junction denervation and attenuated pathologic alterations in ventral roots at late-stage disease. These data suggest that peripheral NRP1 signaling is involved in the pathobiology of this ALS model and that antagonizing Sema3A/NRP1 binding or downstream signals could have implications for the treatment of ALS.

SUBMITTER: Venkova K

PROVIDER: S-EPMC4072440 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Venkova Kalina K Christov Alexander A Kamaluddin Zarine Z Kobalka Peter P Siddiqui Saaid S Hensley Kenneth K

Journal of neuropathology and experimental neurology 20140701 7

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive distal axonopathy that precedes actual motor neuron death. Triggers for neuromuscular junction degeneration remain to be determined, but the axon repulsion factor semaphorin 3A (Sema3A), which is derived from terminal Schwann cells, is a plausible candidate. This study examines the hypothesis that Sema3A signaling through its motor neuron neuropilin-1 (NRP1) receptor triggers distal axonopathy and muscle d ...[more]

PMID: 24918638

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Project description:The rate of disease progression in amyotrophic lateral sclerosis (ALS) is highly variable, even between patients with the same genetic mutations. Metabolic alterations may affect disease course variability in ALS patients, but challenges in identifying the preclinical and early phases of the disease limit our understanding of molecular mechanisms underlying differences in the rate of disease progression. We examined effects of SOD1G93A on thoracic and lumbar spinal cord metabolites in two mouse ALS models with different rates of disease progression: the transgenic SOD1G93A-C57BL/6JOlaHsd (C57-G93A, slow progression) and transgenic SOD1G93A-129SvHsd (129S-G93A, fast progression) strains. Samples from three timepoints (presymptomatic, disease onset, and late stage disease) were analyzed using Gas Chromatography-Mass Spectrometry metabolomics. Tissue metabolome differences in the lumbar spinal cord were driven primarily by mouse genetic background, although larger responses were observed in metabolic trajectories after the onset of symptoms. The significantly affected lumbar spinal cord metabolites were involved in energy and lipid metabolism. In the thoracic spinal cord, metabolic differences related to genetic background, background-SOD1 genotype interactions, and longitudinal SOD1G93A effects. The largest responses in thoracic spinal cord metabolic trajectories related to SOD1G93A effects before onset of visible symptoms. More metabolites were significantly affected in the thoracic segment, which were involved in energy homeostasis, neurotransmitter synthesis and utilization, and the oxidative stress response. We find evidence that initial metabolic alterations in SOD1G93A mice confer disadvantages for maintaining neuronal viability under ALS-related stressors, with slow-progressing C57-G93A mice potentially having more favorable spinal cord bioenergetic profiles than 129S-G93A. These genetic background-associated metabolic differences together with the different early metabolic responses underscore the need to better characterize the impact of germline genetic variation on cellular responses to ALS gene mutations both before and after the onset of symptoms in order to understand their impact on disease development.

Project description:Amyotrophic Lateral Sclerosis (ALS) is an adult-onset and fast progression neurodegenerative disease that leads to the loss of motor neurons. Mechanisms of selective motor neuron loss in ALS are unknown. The early events occurring in the spinal cord that may contribute to motor neuron death are not described, neither astrocytes participation in the pre-symptomatic phases of the disease. In order to identify ALS early events, we performed a microarray analysis employing a whole mouse genome platform to evaluate the gene expression pattern of lumbar spinal cords of transgenic SOD1G93A mice and their littermate controls at pre-symptomatic ages of 40 and 80 days. Differentially expressed genes were identified by means of the Bioconductor packages Agi4x44Preprocess and limma. FunNet web based tool was used for analysis of over-represented pathways. Furthermore, immunolabeled astrocytes from 40 and 80 days old mice were submitted to laser microdissection and RNA was extracted for evaluation of a selected gene by qPCR. Statistical analysis has pointed to 492 differentially expressed genes (155 up and 337 down regulated) in 40 days and 1105 (433 up and 672 down) in 80 days old ALS mice. The KEGG pathways tight junction, antigen processing and presentation, oxidative phosphorylation, endocytosis, chemokine signaling pathway, ubiquitin mediated proteolysis and glutamatergic synapse were found over-represented at both 40 and 80 days pre-symptomatic ages. Ube2i gene expression was evaluated in astrocytes from both transgenic ages, being up regulated in 40 and 80 days astrocytes enriched samples. Our data points to important early molecular events occurring in pre-symptomatic phases of ALS in mouse model. Early SUMOylation process linked to astrocytes might account to non autonomous cell toxicity in ALS. Further studies on the signaling pathways presented here may provide new insights to better understand the events triggering motor neuron death in this devastating disorder.

Dataset Information

Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Publications

Semaphorin 3A signaling through neuropilin-1 is an early trigger for distal axonopathy in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

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