Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3–5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment.Results: Motoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12.Conclusions: Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

“…Csf3r (log2FC: 0.96; adjusted p -value < 0.01) and Csf2rb (log2FC: 0.96; adjusted p -value < 0.01), coding for the receptors of granulocyte (G-CSF) and granulocyte-macrophage stimulating factor (GM-CSF), were significantly up-regulated the SOD1 G86R group. The hematopoietic factor G-CSF, ligand of Csf3r, is neuroprotective in SOD1 G93A mice (Henriques et al, 2011 ) and is able to re-adjust gene expression in lumbar motor neurons (Henriques et al, 2015c ).…”

“…Prss12 , or motopsin, is a neuronal protease which positively regulates axonal plasticity (Mitsui et al, 2013 ). Prss12 expression is known to be down-regulated during acute stress (Numajiri et al, 2006 ) and in laser-captured SOD1 G93A motoneurons (Henriques et al, 2015c ). Down-regulation of Prss12 in SOD1 G86R mice could therefore relate to axonal dysfunction.…”

Disrupting SOD1 activity inhibits cell growth and enhances lipid accumulation in nasopharyngeal carcinoma

“…6 ). Moreover, CPT1A downregulation has been observed in SOD1 G93A cells [ 29 ]. Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects of radiotherapy in NPC patients [ 21 ].…”

Analytical sequence to study G-CSF effect on the transcriptome of isolated spinal motoneurons from SOD1 G93A mice, an animal model for amyotrophic lateral sclerosis

“…Many studies have undertaken the study of the transcriptome of tissues or isolated cells from animal models or ALS patients [4] . The aim of the original study was to identify for the first time the transcriptional changes in motoneurons from SOD1 G93A mice upon G-CSF treatment [1] .…”

“…In an attempt to identify specific transcriptomic deregulation with biological relevance by ANOVA, we applied another filtering step, consisting in removing all transcripts with a fold-change expression lower than 1.2 when comparing non-transgenic and SOD1 G93A samples. The results generated by the discriminant analysis and by ANOVA are detailed in the original manuscript [1] .…”