Remodeling of astrocyte secretome in amyotrophic lateral sclerosis: uncovering novel targets to combat astrocyte-mediated toxicity

Amyotrophic lateral sclerosis (ALS) is an adult-onset paralytic disease characterized by progressive degeneration of upper and lower motor neurons in the motor cortex, brainstem and spinal cord. Motor neuron degeneration is typically caused by a combination of intrinsic neuronal (cell autonomous) defects as well as extrinsic (non-cell autonomous) factors such as astrocyte-mediated toxicity. Astrocytes are highly plastic cells that react to their microenvironment to mediate relevant responses. In neurodegeneration, astrocytes often turn reactive and in turn secrete a slew of factors to exert pro-inflammatory and neurotoxic effects. Various efforts have been carried out to characterize the diseased astrocyte secretome over the years, revealing that pro-inflammatory chemokines, cytokines and microRNAs are the main players in mediating neuronal death. As metabolomic technologies mature, these studies begin to shed light on neurotoxic metabolites such as secreted lipids. In this focused review, we will discuss changes in the astrocyte secretome during ALS. In particular, we will discuss the components of the reactive astrocyte secretome that contribute to neuronal death in ALS.