Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract

Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1 mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3) cells - choline acetyltransferase (ChAT) α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1) microglia, and S100β astrocytes in SOD1 mice. The FCs of pSTAT3 microglia and pSTAT3 astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3 α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3 α-motoneurons compared with pSTAT3 α-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3 α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3 microglia were increased in LPS-treated mice. The FCs of pSTAT3 astrocytes were higher in SOD1 mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.

The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration

“…Loss of the PPIase activity of Ranbp2 in mice promotes a post-transcriptional decline of hnRNPA2B1 levels [239], whereas novel small molecules against the PPIase pocket of CY of Ranbp2 promote a decline of hnRNPA2B1 in HeLa cells [240]. Hence, Ranbp2 emerges as a therapeutic target to control the pathogenicity of mutations in hnRNPA2B1 and the neuroprotection potential of other substrates, such as Stat3, in ALS [240,332].…”

<p>MiRNA-532-5p Regulates CUMS-Induced Depression-Like Behaviors and Modulates LPS-Induced Proinflammatory Cytokine Signaling by Targeting STAT3</p>

“…16 Existing evidence has showed that in microglia and macrophages, high expression of STAT3 inhibits the excessive activation of microglia. 17 Some studies have suggested that the secretion of inflammatory cytokines by the activated immune system is related to the occurrence of depression. 18 There is a certain relationship between the secretion of inflammatory cytokines by the activated immune system.…”

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

“…Therefore, the SOD1*G93A ALS mouse model on a C57Bl/6 genetic background was chosen [17,18,26,45]. These mice exhibit the first measurable deficits in motoric performance at age 8.5 weeks [41], which is by definition within the pre-symptomatic phase [46]. Using the SHIRPA test battery, we were able to confirm these early motor deficits of the mouse line in house ( Figure S3).…”

“…Due to this limitation only sufficiently large groups of female mice were available for this treatment study. Progenies were analysed for presence of the human SOD1 gene by quantitative PCR, as previously described [46]. Copy numbers of the transgene were checked by calculation of the delta cycle threshold (∆CT) = CT internal control − CT gene of interest .…”