GJA1/CX43 High Expression Levels in the Cervical Spinal Cord of ALS Patients Correlate to Microglia-Mediated Neuroinflammatory Profile

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motoneurons (MNs) with a fatal outcome. The typical degeneration of cortico-spinal, spinal, and bulbar MNs, observed in post-mortem biopsies, is associated with the activation of neuroimmune cells. GJA1, a member of the connexins (Cxs) gene family, encodes for connexin 43 (Cx43), a core gap junctions (GJs)- and hemichannels (HCs)-forming protein, involved in cell death, proliferation, and differentiation. Recently, Cx43 expression was found to play a role in ALS pathogenesis. Here, we used microarray and RNA-seq datasets from the NCBI of the spinal cord of control (NDC) and ALS patients, which were stratified according to the GJA1 gene expression. Genes that positively or negatively correlated to GJA1 expression were used to perform a genomic deconvolution analysis (GDA) using neuroimmune signatures. Expression analysis revealed a significantly higher GJA1 expression in the MNs of ALS patients as compared to NDC. Gene deconvolution analysis revealed that positively correlated genes were associated with microglia activation, whereas negatively correlated genes were associated with neuronal activation profiles. Moreover, gene ontology analysis, performed on genes characterizing either microglia or neuronal signature, indicated immune activation or neurogenesis as main biological processes. Finally, using a synthetic analysis of drugs able to revert the GJA1 transcriptomic signatures, we found a specific drug profile for ALS patients with high GJA1 expression levels, composed of amlodipine, sertraline, and prednisolone. In conclusion, our exploratory study suggests GJA1 as a new neuro-immunological gene correlated to microglial cellular profile in the spinal cord of ALS patients. Further studies are warranted to confirm these results and to evaluate the therapeutic potential of drugs able to revert typical GJA1/CX43 signature in ALS patients

Neurotrophic and immunomodulatory effects of olfactory ensheathing cells as a strategy for neuroprotection and regeneration

“…In addition, although a significant increase of Nestin, PGP 9.5, Synapsin I, and GFAP was reported, MAP2 was identified as the most representative, thus suggesting a greater tendency toward the neuronal phenotype (93). This result is confirmed by another study where a neural-like connexin expression was induced in ASCs after OEC-CM treatment (94)(95)(96)(97)(98). On the other hand, when ASCs were co-cultured with OECs using 3D collagen scaffolds, they differentiated into cells with OEC-like morphology and were reported to be p75NTR and Nestin positive and GFAP negative.…”

The Role of Epigenetics in Neuroinflammatory-Driven Diseases

“…Neuroinflammation has been highlighted as an outstanding factor for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple sclerosis (MS) progression. In this regard, the main histopathological feature characterizing neurodegenerative disorders is an aberrant protein conformation resulting in its abnormal intercellular communication, impaired cell differentiation, and neuroanatomical distribution [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Depending on the nature of the accumulated protein, neurodegenerative diseases have been defined as amyloidosis, tauopathies, α-synucleinopathies, and transactivation response DNA binding protein 43 (TDP-43) proteinopathies [ 1 ].…”