Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motoneurons. ALS leads to muscle atrophy, progressive paralysis and death within 3 years post diagnosis. A vast amount of data demonstrated the non-cell autonomous mechanisms in ALS, driven by reactive glia, infiltrating immune cells and peripheral immune activation. The role of NK cells in ALS remains poorly understood, and available data lacks consistency. Our aim was to investigate the role of these lymphocytes in an ALS mouse model SOD1 G93A expressing a GFP marker under the control of the Ncr1 promoter, a marker suited for NK cells studies. Our work shows that in our ALS model, NK lymphocytes do not, or marginally, infiltrate the spinal cord, do not undergo modifications regarding phenotype or activation and that ablation of the cytotoxic receptor Ncr1 has no effect on disease occurence or progression in vivo. We also studied the role of Properdin, a circulating glycoprotein mainly produced by leukocytes, in the SOD1 G93A ALS mouse model. While its role in the complement system is predominantly studied, Properdin can also serve as a recognition protein for apoptotic and necrotic cells to trigger their clearance through a process called opsonization. We established that Properdin accumulates in the spinal cord of our symptomatic SOD1 G93A mice in the form of large aggregates. These aggregates colocalize with aggregates of the misfolded form of the human SOD1 protein and are often wrapped by CD68+ phagocytic microglial cells. In addition, we also find Properdin associated with chromatin-decondensed cells, identified as the highly toxic subpopulation of astrocytes known as Aba astrocytes. Put together, our findings suggest a role of Properdin in the opsonization and clearance of pro-inflammatory elements such as aggregated proteins and degenerating astrocytes. To this day, we do not know the molecular pathways involved in the recognition of Properdin by phagocytes and in its elimination as a complex.