Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.
['Bonfanti|Elisabetta|E|0000-0003-1280-9109', 'Bonifacino|Tiziana|T|', 'Raffaele|Stefano|S|0000-0002-2734-5418', 'Milanese|Marco|M|0000-0003-3384-0666', 'Morgante|Erica|E|', 'Bonanno|Giambattista|G|0000-0003-3744-5786', 'Abbracchio|Maria P|MP|', 'Fumagalli|Marta|M|0000-0002-0158-842X']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D002454:Cell Differentiation D049109:Cell Proliferation D004195:Disease Models, Animal D005260:Female D051379:Mice D008822:Mice, Transgenic D009046:Motor Neurons D009186:Myelin Sheath D009419:Nerve Tissue Proteins D019636:Neurodegenerative Diseases D000073637:Oligodendrocyte Precursor Cells D009836:Oligodendroglia D043562:Receptors, G-Protein-Coupled D013116:Spinal Cord D013482:Superoxide Dismutase D000072105:Superoxide Dismutase-1 D015854:Up-Regulation
oligodendrocytes amyotrophic lateral sclerosis (ALS) G protein-coupled receptor 17 (GPR17) SOD1G93A ALS mouse model montelukast