A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation

Abstract

Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis.

Replication of Genome-Wide Association Analysis Identifies New Susceptibility Loci at Long Noncoding RNA Regions for Vogt-Koyanagi-Harada Disease

“…ABL2 plays an important role in the proliferation and invasion of cancer cells 36 and although a potential role of ABL2 has been reported in immune disorders such as multiple sclerosis and diabetes, the exact role of ABL2 in these diseases is not yet clear. 49,50 The findings presented here suggest that the rs3829794 CC genotype, which protects against acquiring VKH, might be due to a decreased expression of ABL2. Recent studies have shown that inhibition of ABL kinases ameliorates experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, 49 which is further supported by our hypothesis.…”

“…49,50 The findings presented here suggest that the rs3829794 CC genotype, which protects against acquiring VKH, might be due to a decreased expression of ABL2. Recent studies have shown that inhibition of ABL kinases ameliorates experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, 49 which is further supported by our hypothesis. This SNP also had an effect on the proliferation of PBMCs and the production of anti-inflammatory cytokines that are potentially involved in the pathogenesis of VKH.…”

Identification of Genetic Predisposition to Sjögren’s Syndrome by Whole Exome Sequencing

“…For example, the products of the four most enriched candidate genes, AQP1, ABL2, CHD3, and RELN, participate in inflammatory activation, cell adhesion and migration, wound healing, and organ regeneration [36][37][38][39][40][41]. In addition, they play important roles in the nervous system and are associated with central and periphery neuropathies [39,[42][43][44][45][46]. Motor proteins, which are the products of another subset of enriched genes, are essential for axonal transportation and function at immunological synapses [47,48].…”

Analysis of multi‐omics data on the relationship between epigenetic changes and nervous system disorders caused by exposure to environmentally harmful substances

“…However, Ras signaling pathway containing ABL2 downregulated by the hsa‐miR‐15 family (miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p) might be involved and hence warrants further investigation. ABL2 encodes the non‐receptor tyrosine kinase ARG; the ARG C‐terminus is a key regulator of actin cytoskeleton rearrangement, 62 which is involved in the stability and morphogenesis of the dendritic spine 63,64 . Hence, ABL2/ARG non‐receptor tyrosine kinase deficiency destabilizes the dendritic arbor and reduces its density by damaging the dendritic spine 27 .…”