Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a neurodegenerative disorder that affects motor neurons in the motor cortex, brain stem, and spinal cord. Genetic mutations in superoxide dismutase 1 (SOD1), TAR DNA binding protein-43 (TDP-43), and fused in sarcoma (FUS) have been linked to familial forms of ALS. These mutations lead to abnormalities in cellular pathways such as RNA metabolism, mitochondrial dysfunction, and glial-mediated neuroinflammation. Astrocytes have been implicated as a contributing factor in ALS pathology and disease progression. Astrocytes in ALS lesions demonstrate altered morphology and gene expression patterns that correlate with a reactive state. Furthermore, astrocytes derived from ALS patients and a SOD1 transgenic mouse model show increased inflammatory cytokine and chemokine gene expression (e.g. CCL2, CCL11, IL-8, CXCL1).
In addition to phenotypic changes, astrocytes in SOD1-ALS models show other features, such as ubiquitinated SOD1 species reflecting defective proteostasis, elevated levels of reactive oxygen species (ROS), and secretion of TGF-β1, which prevents neuroprotective functions of microglia and T cells. Furthermore, astrocytes in the spinal cord of SOD1 mice and sporadic ALS patients, have elevated levels of the gap junction protein, connexin 43, leading to increased intracellular calcium levels and toxicity in motor neurons.