Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential

SIMPLE SUMMARY: Amyotrophic lateral sclerosis (ALS) is a disease characterized by the death of motor neurons that results in progressive muscle weakness and paralysis. Therefore, much of ALS research has heavily centered on addressing the role of motor neurons in explaining the ALS disease process. However, accumulating evidence has suggested that non-neuronal cells, such as microglia and astrocytes, are actively involved in the disease process. This is currently an active field of research, and we sought to review the landmark discoveries in animal and human cell models regarding the important functions of microglia and astrocytes in ALS, how researchers define their various disease characteristics, and how these cells can be targeted for therapeutics. ABSTRACT: Microglial and astrocytic reactivity is a prominent feature of amyotrophic lateral sclerosis (ALS). Microglia and astrocytes have been increasingly appreciated to play pivotal roles in disease pathogenesis. These cells can adopt distinct states characterized by a specific molecular profile or function depending on the different contexts of development, health, aging, and disease. Accumulating evidence from ALS rodent and cell models has demonstrated neuroprotective and neurotoxic functions from microglia and astrocytes. In this review, we focused on the recent advancements of knowledge in microglial and astrocytic states and nomenclature, the landmark discoveries demonstrating a clear contribution of microglia and astrocytes to ALS pathogenesis, and novel therapeutic candidates leveraging these cells that are currently undergoing clinical trials.